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© 2002 American Society for Clinical Oncology
Molecular Biology of Anaplastic Lymphoma Kinase–Positive Anaplastic Large-Cell LymphomaByFrom the Department of Pathology, Brigham and Women’s Hospital, Boston, MA. Address reprint requests to Jon C. Aster, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115; email: jaster{at}rics.bwh.harvard.edu
ABSTRACT: Anaplastic large-cell lymphoma (ALCL) provides an excellent example of how molecular insights into tumor pathogenesis are influencing and improving tumor classification. ALCL was described initially as a subtype of T-cell/null-cell lymphoma characterized by unusual tumor cell morphology and the expression of CD30. However, it was soon recognized that a subset of ALCLs contained chromosomal translocations involving anaplastic lymphoma kinase (ALK), a novel receptor tyrosine kinase gene. These rearrangements create chimeric genes encoding self-associating, constitutively active ALK fusion proteins that activate a number of downstream effectors, including phospholipase C-gamma, phosphoinositol 3'-kinase, RAS, and signal transducer and activator of transcription proteins, all of which seem potentially important in cellular transformation. Not all tumors classified as ALCLs have ALK rearrangements and, conversely, ALK rearrangements occur in lymphomas of widely varying morphology. Hence, only molecular markers can reliably identify ALK+ ALCL. The importance of doing so is reflected by clinical studies suggesting that ALK+ ALCLs have a significantly better prognosis than other aggressive peripheral T-cell or B-cell lymphomas, including ALK- ALCLs. The unique molecular pathogenesis of ALK+ ALCL is likely to lead to novel therapeutic approaches directed at specific inhibition of ALK or downstream effectors.
THE IDENTIFICATION AND characterization of genes involved by recurrent chromosomal translocations has played a central role in understanding the pathogenesis of hematolymphoid neoplasia. Because these genetic events typically create oncogenes that initiate cellular transformation and, in collaboration with other genetic or epigenetic changes, dictate tumor biology, the presence of particular translocations often correlates well with clinical behavior and outcome. As a result, tests for specific chromosomal translocations (or their molecular consequences) are playing an increasingly important role in the diagnosis and classification of hematolymphoid neoplasms. This role will undoubtedly increase further with the advent of therapies directed at targets created by tumor-specific genetic aberrations. One current example demonstrating how molecular pathology is altering and improving lymphoma classification lies within the diagnostic category known as anaplastic large-cell lymphoma (ALCL). This entity was initially recognized by the presence of the Ki-1 antigen, later designated CD30, on a subset of diffuse large-cell lymphomas characterized by bizarre, highly pleomorphic cytologic features and an unusual tendency to grow within lymph node sinuses, thus simulating metastatic solid tumors, such as carcinoma, melanoma, and even seminoma.1 Some ALCLs were thought originally to be derived from cells of monocyte/macrophage lineage, but on subsequent immunophenotyping2-4 and gene rearrangement studies5,6 most were definitively shown to be of T-cell origin. On the basis of these features, the Kiel classification introduced the diagnostic entity Ki-1+ anaplastic large-cell lymphoma in 1988.7 It was evident early on, however, that CD30 was expressed in a diverse group of neoplasms, some of which overlapped morphologically, and immunophenotypically, with ALCL. The Ki-1 antigen was initially detected on a Hodgkin’s disease cell line8 and is uniformly expressed by Reed-Sternberg cells in classic forms of Hodgkin’s disease. ALCLs were observed to often contain tumor cells resembling Reed-Sternberg cells, leading to speculation about the possible relationship of ALCL and Hodgkin’s disease.1 It was also noted that other neoplasms, including cutaneous T-cell proliferations (eg, lymphomatoid papulosis),1,9,10 enteropathy-associated T-cell lymphoma,11 and large T-cell lymphoma arising in the setting of mycosis fungoides,12,13 frequently express CD30 and sometimes bear a morphologic resemblance to ALCL. The relationship of these diverse entities has been clarified in part by the identification of chromosomal translocations involving the anaplastic lymphoma kinase (ALK) gene in a subset of tumors with ALCL morphology. Most ALK-associated lymphomas present in children or young adults as systemic disease with nodal involvement. ALK rearrangements do not seem to be present in Hodgkin’s disease,14-25 anaplastic cutaneous CD30+ T-cell proliferations, or ALCL-like CD30+ tumors arising secondary to other T-cell malignancies such as mycosis fungoides.17,18,22,26-30 Furthermore, most primary systemic CD30+ ALCLs of older adults also lack ALK rearrangements. Of clinical and diagnostic importance, lymphomas with ALK rearrangements appear to have a significantly better prognosis than other systemic large-cell lymphomas (including systemic ALCLs lacking ALK rearrangements),20,31-35 and a much more varied morphologic appearance than originally appreciated.20,33-37 On the basis of these findings, three groups of neoplasms with ALCL-like morphology are currently recognized, each with a different natural history: primary systemic ALK+ ALCL, primary systemic ALK- ALCL, and primary cutaneous ALCL. This review focuses on the molecular pathogenesis of the most distinctive and best characterized of these entities, ALK+ ALCL.
In the late 1980s, several groups noted that some CD30+ ALCLs were associated with a balanced (2;5)(p23;q35) chromosomal translocation.38-42 Subsequent cloning of the chromosomal breakpoints showed that the affected genes were ALK, located at chromosome 2p23, and NPM (encoding nucleophosmin), located at 5q35.43 The t(2;5) is the most common karyotypic aberration involving ALK, being present in approximately 75% of the ALCLs with ALK rearrangements.44 In the remaining approximate 25% of cases, a number of variant rearrangements involving 2p23 are seen, including t(1;2)(q21;p23), inversion 2(p23;q35), t(2;3)(p23;q21), t(2;17)(p23;q23), and t(X;2)(q11-12;p23) (Table 1). These uncommon rearrangements result in the juxtaposition of ALK with one of a diverse collection of partner genes, which include TPM3, encoding a nonmuscle tropomyosin; TFG (TRCK fusion gene), encoding a polypeptide with a predicted coiled:coiled domain; ATIC, which encodes an enzyme, 5-aminoimidazole-4-carboximide-1-ß-D-ribonucleotide transformylase/inosine monophosphate cyclohydrolase, that participates in purine metabolism; CLTC, encoding the clathrin heavy-chain gene; and MSN, encoding moesin, a member of the protein 4.1 family of membrane-associated polypeptides.
Work from many laboratories has shown that oncogenic rearrangements of receptor tyrosine kinase genes are commonly found in a range of human neoplasms. In the vast majority of such rearrangements, one DNA breakpoint falls within intronic sequences of the involved receptor tyrosine kinase gene and splits the gene in two, dissociating most or all of the 5' extracellular coding sequences and promoter elements from 3' coding sequences for the intracellular signaling domain. The second DNA breakpoint typically falls within the 3' portion of genes that encode structurally diverse polypeptides that appear to share only one feature: the ability to self-associate. Rejoining of DNA in trans thus results in the creation of a chimeric gene with heterologous 5' promoter elements and coding sequences for a self-association domain fused to 3' receptor tyrosine kinase coding sequences for the intracellular signaling domain. Normal activation of receptor tyrosine kinases is dependent on ligand-induced oligomerization.45 In contrast, oncogenic receptor tyrosine kinase fusion proteins self-associate in a ligand-independent fashion, and are therefore constitutively active. In addition, strong chimeric 5' promoter elements often drive high levels of receptor tyrosine kinase fusion gene expression. The net effect of these alterations is to exaggerate and dysregulate otherwise normal downstream signals, which promote cellular transformation. Each of these themes also holds for the ALK rearrangements seen in ALCL, which produce fusion genes encoding self-associating constitutively active ALK tyrosine kinases. The genomic consequences of the most frequent chromosomal aberration in ALK+ ALCL, the t(2;5), are outlined in Fig 1. Intact ALK spans approximately 315 kb and has 26 exons. Much of the gene consists of two large introns (introns 1 and 2), which together measure approximately 170 kb in size. ALK normally gives rise to an mRNA transcript of about 6.5 kb encoding a 205-kDa type I transmembrane glycoprotein, ALK, which is a member of the insulin receptor superfamily of receptor tyrosine kinases.46,47 ALK is normally expressed only within the developing and mature nervous system17,46,47; it is not expressed in normal lymphoid cells, a point that has important diagnostic implications, as will be described. Alk knockout mice are not noticeably developmentally abnormal,48 and the function of ALK is currently unknown.
Normal NPM spans approximately 25 kb and contains 12 exons,49 which encode a ubiquitous, highly expressed 37-kDa phosphoprotein. NPM exists in cells as a homohexamer that shuttles ribonuclear complexes between the nucleolus and the cytoplasm, thereby playing a role in ribosome assembly.50-52 As might be anticipated given the importance of protein synthesis in growth, the expression of NPM is increased when cell division and growth are stimulated.53-59 In the t(2;5), the chromosomal breakpoints consistently fall within intron 4 of NPM, which spans 911 bp,49 and intron 16 of ALK, which spans 2,094 bp. The reciprocal recombination event produces a NPM/ALK gene on the chromosome 5 derivative and a ALK/NPM gene on the chromosome 2 derivative, both of which have the potential to produce chimeric mRNAs. However, only the NPM promoter is active in lymphoid cells, and thus only the NPM/ALK fusion transcript is detected in ALCLs at appreciable levels.43,60,61 The NPM/ALK fusion transcript encodes a chimeric polypeptide of 80 kDa (p80) consisting of the N-terminal portion (amino acids 1 to 117) of NPM and the C-terminal 563 amino acids of ALK, which includes virtually the entire ALK intracellular domain.43 The portion of NPM in the fusion polypeptide includes the NPM self-association domain,62 which is responsible for the formation of higher order NPM/ALK oligomers in the nucleus, and cytoplasm of NPM/ALK-expressing cells.62 These NPM/ALK fusion proteins are also heavily phosphorylated on tyrosine residues, consistent with constitutive activation of the ALK tyrosine kinase.62,63 Other ALK fusion genes and proteins are less well-characterized biochemically, but each share the capacity for self-association (Table 1). TFG and TPM3 were initially identified as being involved in chromosomal translocations in papillary thyroid carcinomas that juxtapose their coding sequences with those of another transmembrane tyrosine kinase, NTRK1.64 The breakpoints in TPM3, located on chromosome 1q21, occur within intron 7 (as in papillary thyroid carcinomas). DNA translocation leads to the formation of a chimeric TPM3/ALK gene encoding a fusion polypeptide consisting of the N-terminal 221 amino acids of TPM3 and the C-terminal 563 amino acids of ALK.65 The TFG gene is located on chromosome 3q21. Because of alternative splicing, the TFG/ALK fusion gene gives rise to two fusion proteins, TFG/ALKL and TFG/ALKS, which contain the N-terminal 193 or 138 amino acids of TFG, respectively, and the C-terminal 563 amino acids of ALK.66 The involved portions of TPM3 and TFG both contain predicted coiled-coil domains that self-associate, and each produce constitutive tyrosine kinase activity when fused to NTRK1.67,68 TFG/ALK also shows constitutive tyrosine kinase activity in vitro,66 and it is hypothesized, on the basis of its ability to dimerize, that the TPM3 fusion partner has similar effects on ALK.65 Like ALK, ATIC is also located on chromosome 2; as a result, rearrangements usually take the form of chromosome 2 inversions. The chimeric gene encodes a 96-kDa fusion protein that includes an N-terminal 229-amino-acid ATIC dimerization domain. When fused to ALK, this ATIC sequence induces constitutive tyrosine kinase and transforming activities.69,70 Another uncommon fusion gene, CLTC/ALK, encodes a 248-kDa polypeptide consisting of most of the clathrin heavy chain (amino acids 1 to 1,634 of 1,675 total) fused to the C-terminal 563 amino acids of ALK.71 The ALK fusion partner in this rearrangement was misidentified initially as a locus on chromosome 22q11.2, CLTCL, which is highly homologous to CLTC; however, the identification of another rearrangement72 and sequencing of the human genome has unambiguously identified CLTC on chromosome 17q23 as the involved gene. Clathrin exists normally as a trimer, suggesting that it also imparts the ability to self-associate when fused to an ALK. Less is known about the recently identified MSN/ALK fusion gene, which encodes a chimeric protein consisting of the N-terminal portion of moesin fused to intracellular ALK.73 However, other members of the protein 4.1 family, such as ezrin, have the capacity for heterodimerization and homodimerization,74,75 and this feature presumably extends to moesin. Finally, Mason et al76 has studied the effect of fusion of the intracellular portion of ALK to a leucine zipper dimerization domain derived from translocated promoter region (TPR) protein. TPR participates in a chromosomal translocation that produces a TPR/MET kinase fusion protein in thyroid carcinomas, but is not known to participate in ALK rearrangements seen in sporadic human cancers. Nonetheless, this artificial TPR-ALK fusion protein has transforming activity that is comparable to that of NPM ALK. In total, these data and the analyses of naturally occurring ALK fusion proteins suggest that covalent coupling of any reasonably strong self-association domain to the intracellular portion of ALK will suffice to create an oncoprotein.
Of interest, the NPM self-association domain also participates in the formation of fusion oncoproteins that do not have tyrosine kinase activity. A t(5;17) seen in a small subset of acute promyelocytic leukemias fuses NPM to the retinoic acid receptor alpha gene (RAR
The effects of NPM/ALK on cultured cells resemble (at least superficially) those of other oncogenic tyrosine kinases such as BCR/ABL and TEL/PDGFßR, which are expressed in typical and atypical forms of chronic myelogenous leukemia, respectively. NPM/ALK confers factor-independent growth on immortalized rodent cell lines, such as NIH-3T3 fibroblasts, 32D myeloid cells, and the pro-B cell line Ba/F3.62,76,81,82 Transforming activity requires both the NPM self-association domain and the tyrosine kinase activity of ALK, as deletions removing the former and mutations abrogating the latter cause loss of function.62,81,82 As might be anticipated from its rather broad transforming activity in vitro, the transforming activity of NPM/ALK in vivo is not limited to T lymphocytes. NPM/ALK induces aggressive B-cell lymphomas when expressed in murine bone marrow progenitor cells.83 More recently, it has been shown that ALK rearrangements may be present in up to 50% of inflammatory myofibroblastic tumors,84-86 rare mesenchymal spindle-cell neoplasms that are typically composed of bland-appearing myofibroblasts mixed with a prominent population of reactive inflammatory cells. Four types of rearrangements that produce ALK fusion proteins have been identified in inflammatory myofibroblastic tumors, two of which involve fusion partners, TPM3 and CLTC,72,87 that are also fused to ALK in some ALCLs (Table 1). The remaining two ALK fusion partners, RANBP2 and TPM4, have only been identified in rearrangements occurring in inflammatory myofibroblastic tumors. Given its apparent capacity to transform a spectrum of cell types, the explanation for the strong association of ALK rearrangements with a specific, limited set of human neoplasms is an intriguing question relevant to many other oncogenic rearrangements as well. Perhaps the ALK gene is particularly prone to DNA breakage in activated T cells, but factors that could produce this type of limited sensitivity to DNA damage are unknown. The NPM/ALK fusion protein localizes partially to the nucleus and nucleolus,62 as the N-terminal NPM domain retains its normal function as a nucleolar transporter,50 raising the possibility that nuclear or nucleolar localization might play a role in cellular transformation. This appears not to be the case, however, as other ALK fusion proteins show predominantly cytoplasmic localization in either diffuse (TPM3/ALK, TFG/ALK, ATIC/ALK) or finely granular (CLTC/ALK) patterns (Table 1). Although activated ALK undoubtedly plays an important role in inducing ALK+ ALCL, as with other oncoproteins, it is probably not sufficient to transform otherwise normal lymphoid cells, as judged by several observations. There is a relatively long lag time between bone marrow reconstitution of mice with activated ALK transgenes and the appearance of ALK+ tumors, which only occur in a subset of mice,83 suggesting that secondary events are needed for lymphomagenesis. In addition, several studies using highly sensitive polymerase chain reaction (PCR) tests have detected evidence of ALK fusion genes in reactive lymphoid tissues and peripheral blood,88,89 which may largely explain some reports suggesting that ALK rearrangements occur in Hodgkin’s disease, and primary cutaneous ALCLs and related lesions. At present, the secondary events that collaborate with ALK in cellular transformation are unknown.
The common feature of diverse ALK fusion proteins is the constitutive activation of ALK signaling (Fig 2). Except for a single variant rearrangement lacking 10 amino acids,90 all fusion proteins include the C-terminal 563 amino acids of ALK. The roles of specific ALK residues in mediating transformation have been evaluated thus far only in vitro. Conclusions drawn from these data must be regarded as preliminary, as in vitro and in vivo requirements for transformation by various oncoproteins, including tyrosine kinases, sometimes differ.91
NPM/ALK tyrosine kinase activity is necessary for cellular transformation.82 A major substrate is NPM/ALK itself, which undergoes transphosphorylation on self-association. There are 21 putative autophosphorylation sites, each serving on phosphorylation as potential docking sites for downstream factors with SH2 or PTB domains, such as phospholipase C-gamma (PLC-  ), SHC, the p85 subunit of phosphoinositol-3'-kinase (PI3K), the adaptor protein GRB2, and other proteins such as insulin receptor substrate 1. Mutation of tyrosine residues 156 and 567 abolishes the binding to insulin receptor substrate 1 and SHC to NPM/ALK, respectively, but has no effect on the transformation of cell lines,81 indicating that these downstream factors are not critical in vitro. These mutations do not affect the binding of the adaptor protein GRB2, which may therefore still contribute to transformation by activating the RAS pathway. NPM/ALK also activates several members of the signal transducer and activator of transcription (STAT) family, including STAT3 and STAT5,48,92 through mechanisms that are not yet defined. Of note, STAT activation is important in certain other forms of hematolymphoid malignancy driven by tyrosine kinase fusion proteins.93,94 Nieborowska-Skorska et al92 have shown that expression of NPM/ALK in cell lines leads to the phosphorylation and nuclear translocation of STAT5. Conversely, a dominant-negative STAT5B mutant inhibits the antiapoptotic and pro-proliferative effects of NPM/ALK in cell lines, and diminishes the growth of NPM/ALK-expressing cell lines after injection into nude mice.
Other data point to the importance of downstream pathways involving PI3K and PLC- Other poorly understood signals may also play a part in NPM/ALK-mediated cellular transformation. Greenland et al97 recently observed that expression of NPM/ALK in a human T-cell line, Jurkat, protected these cells from drug-induced, but not FAS-induced, apoptosis. NPM/ALK tyrosine kinase activity was required for this protective effect, but PI3K activation was not, indicating the existence of NPM/ALK survival signals that appear to be independent of the PKB/akt pathway.
The role of CD30, a member of the tumor necrosis factor receptor family that is uniformly expressed by ALK+ ALCL, has also been the subject of considerable investigation, but its contribution to the transformed phenotype remains unclear. Physical association between CD30 and NPM/ALK has been demonstrated63 and is mediated by the intracellular domain of CD30 and the ALK portion of the fusion protein.98 Although this interaction may result in altered subcellular localization of the NPM/ALK fusion protein, NPM/ALK activity does not appear to be affected appreciably. Furthermore, activation of CD30 enhances neither NPM-ALK autophosphorylation nor phosphorylation of PLC-
Because the ALK promoter is not active in lymphoid cells, the immunodetection of ALK protein in a lymphoid tumor correlates in nearly 100% of cases with the presence of chromosomal translocations involving ALK that place its expression under the control of heterologous promoter elements. As a result, immunohistochemical stains for the intracellular portion of ALK constitute a highly sensitive test for identification of lymphomas with ALK rearrangements (Fig 3A). In tumors expressing the common NPM/ALK fusion protein, staining is usually nuclear and cytoplasmic, whereas variant fusion proteins produce diffuse or punctate cytoplasmic immunoreactivity, making it possible to distinguish NPM from non-NPM rearrangements on the basis of staining patterns (Table 1). Other immunophenotypic markers are also diagnostically helpful. In addition to CD30 (Fig 3B), ALK+ ALCLs often express epithelial membrane antigen,100,101 and are usually positive for one or more markers of cytotoxic T cells,102,103 the presumed cell of origin.
The availability of specific immunohistochemical tests for ALK protein has made it apparent that the histologic spectrum of ALK+ ALCL is broader than initially appreciated. Several morphologies have been described, including common (Fig 3C), lymphohistiocytic, and small-cell variants that differ in cell size and the composition of the accompanying reactive component.101,104,105 Tumor cells may be inconspicuous when they are small in size or present as only a minor cell population, and the small-cell variant may be only focally and weakly positive for CD30, leading to diagnostic difficulties.101,106 In most cases of ALK+ ALCL, characteristic hallmark cells with irregular, eccentric, embryoid, or horseshoe shaped nuclei, variably distinct nucleoli, and large amounts of cytoplasm are present (Fig 3C and 3D).107 However, such cells are not specific for ALK+ ALCL, as they may be seen in systemic ALK- ALCL, cutaneous ALK- ALCL, and even an unusual subset of diffuse large B-cell lymphomas, which as a group appear to have ALK rearrangements rarely, if ever. In addition, ALCLs showing the greatest anaplasia are most often ALK-.20 It is estimated that only 30% to 50% of classic pleomorphic ALCLs are ALK+, whereas ALK positivity is seen in more than 80% of monomorphous ALCLs, more than 75% of small-cell ALCLs, and more than 60% of lymphohistiocytic ALCLs.44 Because of this variability in morphology of ALK+ ALCL, the only reliable diagnostic tests are those that detect ALK rearrangements or their consequences. Because of this, it has been suggested that ALKoma, or ALK+ lymphoma, are more appropriate designations than ALK+ ALCL,34,101,108,109 but for now the name stands. Although highly sensitive,16,17,20,24,29,35,101,105,110-112 immunohistochemical staining for ALK is not entirely specific for tumors with ALK rearrangements. Rarely, diffuse large B-cell lymphomas express full-length ALK.113 The basis for ALK expression is not known, but the behavior of these unusual B-cell tumors appears to be distinct from that of ALK+ ALCLs,35 and they are considered a variant of diffuse large B-cell lymphoma. Interestingly, ALK is also expressed in neural cell lines, neuroblastomas,114 and rhabdomyosarcomas,47 and is detected by immunohistochemistry in inflammatory myofibroblastic tumors associated with ALK rearrangements.72,84,87 These other types of ALK+ neoplasms are usually easily distinguished by other criteria from ALK+ ALCLs and do not present diagnostic difficulties. ALK rearrangements can also be identified with reverse transcriptase PCR, DNA-PCR, fluorescence in situ hybridization (FISH), and Southern blotting. As all reported breakpoints in NPM and ALK occur within the same pair of small introns,19,30 it is possible to detect t(2;5)-NPM/ALK rearrangements by either RNA- or DNA-based PCR methods using single sets of ALK and NPM primers.19,30,115 However, current PCR assays will not detect the approximately 25% of tumors with variant ALK rearrangements, and are potentially confounded (if not carefully controlled) by ALK rearrangements occurring at low frequency in nontransformed cells.88,89 FISH performed with break-apart probes that span the ALK locus will identify all tumors with rearrangements (Fig 4), and can be coupled to morphologic inspection to ensure that ALK rearrangements are occurring within the tumor cell population, giving it distinct advantages over PCR-based assays. However, the sensitivity and specificity of ALK immunohistochemistry using the ALK-1 antibody is comparable to FISH.37 Because immunohistochemistry can be applied to routinely fixed and processed tissues, and paraffin-embedded archival tissues, it is the test of choice for identifying tumors with ALK rearrangements.
A number of clinical studies have supported the view that ALK+ ALCL is a clinicopathologic entity distinct from ALK- systemic ALCL or ALK- cutaneous ALCL. ALK+ ALCL is most common in the first three decades of life and demonstrates a striking male predominance (male/female ratio, 6.5 in the second and third decades).17,20,34 In contrast, ALK- ALCL is a disease of older individuals and demonstrates no sex predilection (male/female ratio, 0.9).34 Most patients with ALK+ ALCL (70%) present with advanced stage disease (stages III to IV) and have B symptoms.116 It frequently involves both nodal and extranodal sites, including (in decreasing order of frequency) skin, bone, soft tissue, lung, and liver. Unlike Hodgkin’s disease, mediastinal involvement by ALK+ ALCL is uncommon. Although involvement of soft tissues is not uncommon in ALK+ ALCL, primary presentations limited to the skin are rarely if ever seen, as judged by the inability to detect evidence of ALK rearrangements in the vast majority of cutaneous CD30+ T-cell lymphoproliferative disorders.18,27 For unclear reasons, primary cutaneous CD30+ ALK- lymphoproliferative disorders follow a variable but generally indolent clinical course,117 despite histologic features that may closely resemble those of aggressive systemic ALK- and ALK+ ALCLs. In most studies, the outcome for patients with ALK+ ALCL has been substantially better than for patients with ALK- ALCL (overall 5-year survival rates of 79% to 88% compared with 28% to 40%, respectively).20,33-35,37 Indeed, it has been suggested that ALK+ ALCL has the best prognosis of any aggressive peripheral B-cell or T-cell neoplasm.118 The relatively young age at presentation may not appear to account for the favorable outcome of ALK+ ALCL, as age was not an independent prognostic indicator in two separate multivariate analyses.34,35 It remains to be demonstrated that this survival advantage extends to the pediatric population, in which one study failed to detect a significant association between ALK expression in ALCL and 2-year event-free survival.16 It does not appear that the type of ALK fusion protein (NPM/ALK or variant) influences outcome.119
ALK+ ALCL presents exciting therapeutic opportunities. On the basis of the treatment experience with the tyrosine kinase inhibitor imatinib mesylate (STI571, Gleevec; Novartis Pharmaceuticals, East Hannover, NJ) in BCR/ABL-induced hematolymphoid malignancies120,121 and gastrointestinal stromal tumors associated with activating mutations in c-KIT,122 ALK represents an excellent therapeutic target in ALK+ ALCL. Lessons learned in the treatment of other neoplasms with tyrosine kinase inhibitors123 are likely to be applied to the treatment of ALK+ ALCL in the future. Indeed, one recent report using cell lines derived from ALK+ ALCLs has shown that inhibition of NPM/ALK tyrosine kinase activity induces programmed cell death.124 It also seems, at least superficially, that many activated tyrosine kinases engage similar downstream signaling pathways, including RAS (via GRB2), PLC- , PI3K/AKT, and STATs, that drive tumor cell growth and survival. Each of these downstream factors is a potential target for therapies that are likely to act synergistically with ALK inhibitors. Thus, although the current outcome in this entity is relatively favorable with standard anthracycline-containing chemotherapy regimens, our improved understanding of the molecular pathogenesis of ALK+ ALCL promises to lead to more specific, effective, and less toxic therapies.
Supported in part by grants nos. CA82308 (to J.C.A.) and P30 CA6516 (to J.L.K) from the National Institutes of Health, Bethesda, MD. We thank Paola dal Cin, PhD, and Geraldine Pinkus, MD, for providing molecular cytogenetic and immunohistochemical materials.
1. Stein H, Mason DY, Gerdes J, et al: The expression of the Hodgkin’s disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: Evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood 66: 848-858, 1985 2. Agnarsson BA, Kadin ME: Ki-1 positive large cell lymphoma: A morphologic and immunologic study of 19 cases. Am J Surg Pathol 12: 264-274, 1988[Medline] 3. Chan JK, Ng CS, Hui PK, et al: Anaplastic large cell Ki-1 lymphoma: Delineation of two morphological types. Histopathology 15: 11-34, 1989[Medline] 4. Chott A, Kaserer K, Augustin I, et al: Ki-1-positive large cell lymphoma: A clinicopathologic study of 41 cases. Am J Surg Pathol 14: 439-448, 1990[Medline] 5. O’Connor NT, Stein H, Gatter KC, et al: Genotypic analysis of large cell lymphomas which express the Ki-1 antigen. Histopathology 11: 733-740, 1987[Medline] 6. Herbst H, Tippelmann G, Anagnostopoulos I, et al: Immunoglobulin and T-cell receptor gene rearrangements in Hodgkin’s disease and Ki-1-positive anaplastic large cell lymphoma: Dissociation between phenotype and genotype. Leuk Res 13: 103-116, 1989[CrossRef][Medline] 7. Stansfeld AG, Diebold J, Noel H, et al: Updated Kiel classification for lymphomas. Lancet 1: 292-293, 1988[Medline] 8. Schwab U, Stein H, Gerdes J, et al: Production of a monoclonal antibody specific for Hodgkin and Sternberg-Reed cells of Hodgkin’s disease and a subset of normal lymphoid cells. Nature 299: 65-67, 1982[CrossRef][Medline] 9. Kadin M, Nasu K, Sako D, et al: Lymphomatoid papulosis: A cutaneous proliferation of activated helper T cells expressing Hodgkin’s disease-associated antigens. Am J Pathol 119: 315-325, 1985[Abstract] 10. Kaudewitz P, Burg G, Stein H, et al: Monoclonal antibody patterns in lymphomatoid papulosis. Dermatol Clin 3: 749-757, 1985[Medline] 11. Isaacson PG: Gastrointestinal lymphomas of T- and B-cell types. Mod Pathol 12: 151-158, 1999[Medline] 12. Kaudewitz P, Stein H, Dallenbach F, et al: Primary and secondary cutaneous Ki-1+ (CD30+) anaplastic large cell lymphomas: Morphologic, immunohistologic, and clinical-characteristics. Am J Pathol 135: 359-367, 1989[Abstract]
13. Banerjee SS, Heald J, Harris M: Twelve cases of Ki-1 positive anaplastic large cell lymphoma of skin. J Clin Pathol 44: 119-125, 1991
14. Elmberger PG, Lozano MD, Weisenburger DD, et al: Transcripts of the npm-alk fusion gene in anaplastic large cell lymphoma: Hodgkin’s disease, and reactive lymphoid lesions. Blood 86: 3517-3521, 1995 15. Downing JR, Ladanyi M, Raffeld M, et al: Large-cell anaplastic lymphoma-specific translocation in Hodgkin’s disease. Lancet 345: 918-921, 1995[Medline]
16. Hutchison RE, Banki K, Shuster JJ, et al: Use of an anti-ALK antibody in the characterization of anaplastic large-cell lymphoma of childhood. Ann Oncol 8: 37-42, 1997
17. Pulford K, Lamant L, Morris SW, et al: Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1. Blood 89: 1394-1404, 1997
18. Wood GS, Hardman DL, Boni R, et al: Lack of the t(2;5) or other mutations resulting in expression of anaplastic lymphoma kinase catalytic domain in CD30+ primary cutaneous lymphoproliferative disorders and Hodgkin’s disease. Blood 88: 1765-1770, 1996 19. Ladanyi M, Cavalchire G, Morris SW, et al: Reverse transcriptase polymerase chain reaction for the Ki-1 anaplastic large cell lymphoma-associated t(2;5) translocation in Hodgkin’s disease. Am J Pathol 145: 1296-1300, 1994[Abstract] 20. Nakamura S, Shiota M, Nakagawa A, et al: Anaplastic large cell lymphoma: A distinct molecular pathologic entity—A reappraisal with special reference to p80(NPM/ALK) expression. Am J Surg Pathol 21: 1420-1432, 1997[CrossRef][Medline]
21. Weiss LM, Lopategui JR, Sun LH, et al: Absence of the t(2;5) in Hodgkin’s disease. Blood 85: 2845-2847, 1995
22. Wellmann A, Otsuki T, Vogelbruch M, et al: Analysis of the t(2;5)(p23;q35) translocation by reverse transcription-polymerase chain reaction in CD30+ anaplastic large-cell lymphomas, in other non-Hodgkin’s lymphomas of T-cell phenotype, and in Hodgkin’s disease. Blood 86: 2321-2328, 1995 23. Hall PA, d’Ardenne AJ, Stansfeld AG: Paraffin section immunohistochemistry: II. Hodgkin’s disease and large cell anaplastic (Ki1) lymphoma. Histopathology 13: 161-169, 1988[Medline]
24. Herbst H, Anagnostopoulos J, Heinze B, et al: ALK gene products in anaplastic large cell lymphomas and Hodgkin’s disease. Blood 86: 1694-1700, 1995 25. Herling M, Rassidakis GZ, Viviani S, et al: Anaplastic lymphoma kinase (ALK) is not expressed in Hodgkin’s disease: Results with ALK-11 antibody in 327 untreated patients. Leuk Lymphoma 42: 969-979, 2001[Medline] 26. Su LD, Schnitzer B, Ross CW, et al: The t(2;5)-associated p80 NPM/ALK fusion protein in nodal and cutaneous CD30+ lymphoproliferative disorders. J Cutan Pathol 24: 597-603, 1997[CrossRef][Medline]
27. DeCoteau JF, Butmarc JR, Kinney MC, et al: The t(2;5) chromosomal translocation is not a common feature of primary cutaneous CD30+ lymphoproliferative disorders: Comparison with anaplastic large-cell lymphoma of nodal origin. Blood 87: 3437-3441, 1996 28. Herbst H, Sander C, Tronnier M, et al: Absence of anaplastic lymphoma kinase (ALK) and Epstein-Barr virus gene products in primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis. Br J Dermatol 137: 680-686, 1997[CrossRef][Medline] 29. Pittaluga S, Wiodarska I, Pulford K, et al: The monoclonal antibody ALK1 identifies a distinct morphological subtype of anaplastic large cell lymphoma associated with 2p23/ALK rearrangements. Am J Pathol 151: 343-351, 1997[Abstract] 30. Sarris AH, Luthra R, Papadimitracopoulou V, et al: Long-range amplification of genomic DNA detects the t(2;5)(p23;q35) in anaplastic large-cell lymphoma, but not in other non-Hodgkin’s lymphomas, Hodgkin’s disease, or lymphomatoid papulosis. Ann Oncol 8: 59-63, 1997
31. Sandlund JT, Pui CH, Roberts WM, et al: Clinicopathologic features and treatment outcome of children with large-cell lymphoma and the t(2;5)(p23;q35). Blood 84: 2467-2471, 1994
32. Sandlund JT, Pui CH, Santana VM, et al: Clinical features and treatment outcome for children with CD30+ large-cell non-Hodgkin’s lymphoma. J Clin Oncol 12: 895-898, 1994
33. Shiota M, Nakamura S, Ichinohasama R, et al: Anaplastic large cell lymphomas expressing the novel chimeric protein p80NPM/ALK: A distinct clinicopathologic entity. Blood 86: 1954-1960, 1995
34. Falini B, Pileri S, Zinzani PL, et al: ALK+ lymphoma: Clinico-pathological findings and outcome. Blood 93: 2697-2706, 1999
35. Gascoyne RD, Aoun P, Wu D, et al: Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma. Blood 93: 3913-3921, 1999
36. Zinzani PL, Bendandi M, Martelli M, et al: Anaplastic large-cell lymphoma: Clinical and prognostic evaluation of 90 adult patients. J Clin Oncol 14: 955-962, 1996 37. Cataldo KA, Jalal SM, Law ME, et al: Detection of t(2;5) in anaplastic large cell lymphoma: Comparison of immunohistochemical studies, FISH, and RT-PCR in paraffin-embedded tissue. Am J Surg Pathol 23: 1386-1392, 1999[CrossRef][Medline] 38. Le Beau MM, Bitter MA, Larson RA, et al: The t(2;5)(p23;q35): A recurring chromosomal abnormality in Ki-1- positive anaplastic large cell lymphoma. Leukemia 3: 866-870, 1989[Medline]
39. Kaneko Y, Frizzera G, Edamura S, et al: A novel translocation, t(2;5)(p23;q35), in childhood phagocytic large T-cell lymphoma mimicking malignant histiocytosis. Blood 73: 806-813, 1989 40. Rimokh R, Magaud JP, Berger F, et al: A translocation involving a specific breakpoint (q35) on chromosome 5 is characteristic of anaplastic large cell lymphoma (‘Ki-1 lymphoma’). Br J Haematol 71: 31-36, 1989[Medline] 41. Mason DY, Bastard C, Rimokh R, et al: CD30-positive large cell lymphomas (‘Ki-1 lymphoma’) are associated with a chromosomal translocation involving 5q35. Br J Haematol 74: 161-168, 1990[Medline] 42. Bitter MA, Franklin WA, Larson RA, et al: Morphology in Ki-1(CD30)-positive non-Hodgkin’s lymphoma is correlated with clinical features and the presence of a unique chromosomal abnormality, t(2;5)(p23;q35). Am J Surg Pathol 14: 305-316, 1990[Medline]
43. Morris SW, Kirstein MN, Valentine MB, et al: Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 263: 1281-1284, 1994 44. Duyster J, Bai RY, Morris SW: Translocations involving anaplastic lymphoma kinase (ALK). Oncogene 20: 5623-5637, 2001[CrossRef][Medline] 45. Rodrigues GA, Park M: Oncogenic activation of tyrosine kinases. Curr Opin Genet Dev 4: 15-24, 1994[CrossRef][Medline] 46. Iwahara T, Fujimoto J, Wen D, et al: Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Oncogene 14: 439-449, 1997[CrossRef][Medline] 47. Morris SW, Naeve C, Mathew P, et al: ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin’s lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK). Oncogene 14: 2175-2188, 1997[CrossRef][Medline] 48. Morris SW, Xue L, Ma Z, et al: Alk+ CD30+ lymphomas: A distinct molecular genetic subtype of non-Hodgkin’s lymphoma. Br J Haematol 113: 275-295, 2001[CrossRef][Medline]
49. Chan PK, Chan FY, Morris SW, et al: Isolation and characterization of the human nucleophosmin/B23 (NPM) gene: Identification of the YY1 binding site at the 5' enhancer region. Nucleic Acids Res 25: 1225-1232, 1997 50. Borer RA, Lehner CF, Eppenberger HM, et al: Major nucleolar proteins shuttle between nucleus and cytoplasm. Cell 56: 379-390, 1989[CrossRef][Medline] 51. Chan WY, Liu QR, Borjigin J, et al: Characterization of the cDNA encoding human nucleophosmin and studies of its role in normal and abnormal growth. Biochemistry 28: 1033-1039, 1989[CrossRef][Medline] 52. Chan PK, Chan FY: Nucleophosmin/B23 (NPM) oligomer is a major and stable entity in HeLa cells. Biochim Biophys Acta 1262: 37-42, 1995[Medline]
53. Feuerstein N, Spiegel S, Mond JJ: The nuclear matrix protein, numatrin (B23), is associated with growth factor-induced mitogenesis in Swiss 3T3 fibroblasts and with T lymphocyte proliferation stimulated by lectins and anti-T cell antigen receptor antibody. J Cell Biol 107: 1629-1642, 1988
54. Feuerstein N, Chan PK, Mond JJ: Identification of numatrin, the nuclear matrix protein associated with induction of mitogenesis, as the nucleolar protein B23: Implication for the role of the nucleolus in early transduction of mitogenic signals. J Biol Chem 263: 10608-10612, 1988 55. Chakrabarty S, Fan D, Varani J: Modulation of differentiation and proliferation in human colon carcinoma cells by transforming growth factor beta 1 and beta 2. Int J Cancer 46: 493-499, 1990[Medline] 56. Peter M, Nakagawa J, Doree M, et al: Identification of major nucleolar proteins as candidate mitotic substrates of cdc2 kinase. Cell 60: 791-801, 1990[CrossRef][Medline] 57. Feuerstein N, Randazzo PA: In vivo and in vitro phosphorylation studies of numatrin, a cell cycle regulated nuclear protein, in insulin-stimulated NIH 3T3 HIR cells. Exp Cell Res 194: 289-296, 1991[CrossRef][Medline] 58. Derenzini M, Sirri V, Trere D, et al: The quantity of nucleolar proteins nucleolin and protein B23 is related to cell doubling time in human cancer cells. Lab Invest 73: 497-502, 1995[Medline] 59. Koike H, Karas RH, Baur WE, et al: Differential-display polymerase chain reaction identifies nucleophosmin as an estrogen-regulated gene in human vascular smooth muscle cells. J Vasc Surg 23: 477-482, 1996[CrossRef][Medline]
60. Beylot-Barry M, Groppi A, Vergier B, et al: Characterization of t(2;5) reciprocal transcripts and genomic breakpoints in CD30+ cutaneous lymphoproliferations. Blood 91: 4668-4676, 1998
61. Cordell JL, Pulford KA, Bigerna B, et al: Detection of normal and chimeric nucleophosmin in human cells. Blood 93: 632-642, 1999 62. Bischof D, Pulford K, Mason DY, et al: Role of the nucleophosmin (NPM) portion of the non-Hodgkin’s lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis. Mol Cell Biol 17: 2312-2325, 1997[Abstract] 63. Shiota M, Fujimoto J, Semba T, et al: Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3. Oncogene 9: 1567-1574, 1994[Medline] 64. Pierotti MA, Bongarzone I, Borrello MG, et al: Rearrangements of TRK proto-oncogene in papillary thyroid carcinomas. J Endocrinol Invest 18: 130-133, 1995[Medline]
65. Lamant L, Dastugue N, Pulford K, et al: A new fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation. Blood 93: 3088-3095, 1999
66. Hernandez L, Pinyol M, Hernandez S, et al: TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations. Blood 94: 3265-3268, 1999 67. Greco A, Mariani C, Miranda C, et al: The DNA rearrangement that generates the TRK-T3 oncogene involves a novel gene on chromosome 3 whose product has a potential coiled-coil domain. Mol Cell Biol 15: 6118-6127, 1995[Abstract] 68. Greco A, Fusetti L, Miranda C, et al: Role of the TFG N-terminus and coiled-coil domain in the transforming activity of the thyroid TRK-T3 oncogene. Oncogene 16: 809-816, 1998[CrossRef][Medline]
69. Trinei M, Lanfrancone L, Campo E, et al: A new variant anaplastic lymphoma kinase (ALK)-fusion protein (ATIC-ALK) in a case of ALK-positive anaplastic large cell lymphoma. Cancer Res 60: 793-798, 2000
70. Colleoni GW, Bridge JA, Garicochea B, et al: ATIC-ALK: A novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35). Am J Pathol 156: 781-789, 2000
71. Touriol C, Greenland C, Lamant L, et al: Further demonstration of the diversity of chromosomal changes involving 2p23 in ALK-positive lymphoma: 2 cases expressing ALK kinase fused to CLTCL (clathrin chain polypeptide-like). Blood 95: 3204-3207, 2000
72. Bridge JA, Kanamori M, Ma Z, et al: Fusion of the ALK gene to the clathrin heavy chain gene, CLTC, in inflammatory myofibroblastic tumor. Am J Pathol 159: 411-415, 2001 73. Tort F, Pinyol M, Pulford K, et al: Molecular characterization of a new ALK translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma. Lab Invest 81: 419-426, 2001[Medline] 74. Gary R, Bretscher A: Ezrin self-association involves binding of an N-terminal domain to a normally masked C-terminal domain that includes the F-actin binding site. Mol Biol Cell 6: 1061-1075, 1995[Abstract] 75. Turunen O, Sainio M, Jaaskelainen J, et al: Structure-function relationships in the ezrin family and the effect of tumor-associated point mutations in neurofibromatosis 2 protein. Biochim Biophys Acta 1387: 1-16, 1998[CrossRef][Medline]
76. Mason DY, Pulford KA, Bischof D, et al: Nucleolar localization of the nucleophosmin-anaplastic lymphoma kinase is not required for malignant transformation. Cancer Res 58: 1057-1062, 1998
77. Redner RL, Chen JD, Rush EA, et al: The t(5;17) acute promyelocytic leukemia fusion protein NPM-RAR interacts with co-repressor and co-activator proteins and exhibits both positive and negative transcriptional properties. Blood 95: 2683-2690, 2000 78. Redner RL, Corey SJ, Rush EA: Differentiation of t(5;17) variant acute promyelocytic leukemic blasts by all-trans retinoic acid. Leukemia 11: 1014-1016, 1997[CrossRef][Medline] 79. Yoneda-Kato N, Look AT, Kirstein MN, et al: The t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute myeloid leukemia produces a novel fusion gene, NPM-MLF1. Oncogene 12: 265-275, 1996[Medline]
80. Hitzler JK, Witte DP, Jenkins NA, et al: cDNA cloning, expression pattern, and chromosomal localization of Mlf1, murine homologue of a gene involved in myelodysplasia and acute myeloid leukemia. Am J Pathol 155: 53-59, 1999
81. Fujimoto J, Shiota M, Iwahara T, et al: Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5). Proc Natl Acad Sci U S A 93: 4181-4186, 1996
82. Bai RY, Dieter P, Peschel C, et al: Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase C-gamma to mediate its mitogenicity. Mol Cell Biol 18: 6951-6961, 1998
83. Kuefer MU, Look AT, Pulford K, et al: Retrovirus-mediated gene transfer of NPM-ALK causes lymphoid malignancy in mice. Blood 90: 2901-2910, 1997
84. Griffin CA, Hawkins AL, Dvorak C, et al: Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. Cancer Res 59: 2776-2780, 1999 85. Coffin CM, Patel A, Perkins S, et al: ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor. Mod Pathol 14: 569-576, 2001[CrossRef][Medline] 86. Yousem SA, Shaw H, Cieply K: Involvement of 2p23 in pulmonary inflammatory pseudotumors. Hum Pathol 32: 428-433, 2001[CrossRef][Medline]
87. Lawrence B, Perez-Atayde A, Hibbard MK, et al: TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. Am J Pathol 157: 377-384, 2000 88. Trumper L, Pfreundschuh M, Bonin FV, et al: Detection of the t(2;5)-associated NPM/ALK fusion cDNA in peripheral blood cells of healthy individuals. Br J Haematol 103: 1138-1144, 1998[CrossRef][Medline]
89. Maes B, Vanhentenrijk V, Wlodarska I, et al: The NPM-ALK and the ATIC-ALK fusion genes can be detected in non-neoplastic cells. Am J Pathol 158: 2185-2193, 2001 90. Ladanyi M, Cavalchire G: Molecular variant of the NPM-ALK rearrangement of Ki-1 lymphoma involving a cryptic ALK splice site. Genes Chromosomes Cancer 15: 173-177, 1996[CrossRef][Medline] 91. Pear WS: Signaling in leukemia: Which messenger to kill? J Clin Invest 105: 419-422, 2000[Medline]
92. Nieborowska-Skorska M, Slupianek A, Xue L, et al: Role of signal transducer and activator of transcription 5 in nucleophosmin/anaplastic lymphoma kinase-mediated malignant transformation of lymphoid cells. Cancer Res 61: 6517-6523, 2001 93. Schwaller J, Parganas E, Wang D, et al: Stat5 is essential for the myelo- and lymphoproliferative disease induced by TEL/JAK2. Mol Cell 6: 693-704, 2000[CrossRef][Medline]
94. Sternberg DW, Tomasson MH, Carroll M, et al: The TEL/PDGFbetaR fusion in chronic myelomonocytic leukemia signals through STAT5-dependent and STAT5-independent pathways. Blood 98: 3390-3397, 2001
95. Bai RY, Ouyang T, Miething C, et al: Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway. Blood 96: 4319-4327, 2000
96. Slupianek A, Nieborowska-Skorska M, Hoser G, et al: Role of phosphatidylinositol 3-kinase-Akt pathway in nucleophosmin/anaplastic lymphoma kinase-mediated lymphomagenesis. Cancer Res 61: 2194-2199, 2001 97. Greenland C, Touriol C, Chevillard G, et al: Expression of the oncogenic NPM-ALK chimeric protein in human lymphoid T-cells inhibits drug-induced, but not Fas-induced apoptosis. Oncogene 20: 7386-7397, 2001[CrossRef][Medline] 98. Hubinger G, Scheffrahn I, Muller E, et al: The tyrosine kinase NPM-ALK, associated with anaplastic large cell lymphoma, binds the intracellular domain of the surface receptor CD30 but is not activated by CD30 stimulation. Exp Hematol 27: 1796-1805, 1999[CrossRef][Medline] 99. Hubinger G, Muller E, Scheffrahn I, et al: CD30-mediated cell cycle arrest associated with induced expression of p21(CIP1/WAF1) in the anaplastic large cell lymphoma cell line Karpas 299. Oncogene 20: 590-598, 2001[CrossRef][Medline] 100. Delsol G, Al Saati T, Gatter KC, et al: Coexpression of epithelial membrane antigen (EMA), Ki-1, and interleukin-2 receptor by anaplastic large cell lymphomas: Diagnostic value in so-called malignant histiocytosis. Am J Pathol 130: 59-70, 1988[Abstract]
101. Benharroch D, Meguerian-Bedoyan Z, Lamant L, et al: ALK-positive lymphoma: A single disease with a broad spectrum of morphology. Blood 91: 2076-2084, 1998
102. Foss HD, Anagnostopoulos I, Araujo I, et al: Anaplastic large-cell lymphomas of T-cell and null-cell phenotype express cytotoxic molecules. Blood 88: 4005-4011, 1996
103. Krenacs L, Wellmann A, Sorbara L, et al: Cytotoxic cell antigen expression in anaplastic large cell lymphomas of T- and null-cell type and Hodgkin’s disease: Evidence for distinct cellular origin. Blood 89: 980-989, 1997 104. Kinney MC, Collins RD, Greer JP, et al: A small-cell-predominant variant of primary Ki-1 (CD30)+ T-cell lymphoma. Am J Surg Pathol 17: 859-868, 1993[Medline]
105. Falini B, Bigerna B, Fizzotti M, et al: ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum. Am J Pathol 153: 875-886, 1998 106. Cheuk W, Hill RW, Bacchi C, et al: Hypocellular anaplastic large cell lymphoma mimicking inflammatory lesions of lymph nodes. Am J Surg Pathol 24: 1537-1543, 2000[Medline] 107. Delsol G, Mason D: ‘Hallmark’ cells in nodal cytotoxic lymphomas. Am J Surg Pathol 24: 1309-1310, 2000[CrossRef][Medline] 108. Pulford K, Morris SW, Mason DY: Anaplastic lymphoma kinase proteins and malignancy. Curr Opin Hematol 8: 231-236, 2001[CrossRef][Medline] 109. Jaffe ES: Anaplastic large cell lymphoma: The shifting sands of diagnostic hematopathology. Mod Pathol 14: 219-228, 2001[CrossRef][Medline]
110. Shiota M, Fujimoto J, Takenaga M, et al: Diagnosis of t(2;5)(p23;q35)-associated Ki-1 lymphoma with immunohistochemistry. Blood 84: 3648-3652, 1994
111. Lamant L, Meggetto F, al Saati T, et al: High incidence of the t(2;5)(p23;q35) translocation in anaplastic large cell lymphoma and its lack of detection in Hodgkin’s disease: Comparison of cytogenetic analysis, reverse transcriptase-polymerase chain reaction, and P-80 immunostaining. Blood 87: 284-291, 1996 112. Pileri SA, Pulford K, Mori S, et al: Frequent expression of the NPM-ALK chimeric fusion protein in anaplastic large-cell lymphoma, lympho-histiocytic type. Am J Pathol 150: 1207-1211, 1997[Abstract]
113. Delsol G, Lamant L, Mariame B, et al: A new subtype of large B-cell lymphoma expressing the ALK kinase and lacking the 2; 5 translocation. Blood 89: 1483-1490, 1997
114. Lamant L, Pulford K, Bischof D, et al: Expression of the ALK tyrosine kinase gene in neuroblastoma. Am J Pathol 156: 1711-1721, 2000 115. Ladanyi M, Cavalchire G: Detection of the NPM-ALK genomic rearrangement of Ki-1 lymphoma and isolation of the involved NPM and ALK introns. Diagn Mol Pathol 5: 154-158, 1996[CrossRef][Medline]
116. Brugieres L, Deley MC, Pacquement H, et al: CD30(+) anaplastic large-cell lymphoma in children: Analysis of 82 patients enrolled in two consecutive studies of the French Society of Pediatric Oncology. Blood 92: 3591-3598, 1998
117. Bekkenk MW, Geelen FA, van Voorst Vader PC, et al: Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: A report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment. Blood 95: 3653-3661, 2000 118. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma: The Non-Hodgkin’s Lymphoma Classification Project. Blood 89:3909-3918, 1997
119. Falini B, Pulford K, Pucciarini A, et al: Lymphomas expressing ALK fusion protein(s) other than NPM-ALK. Blood 94: 3509-3515, 1999
120. Druker BJ, Sawyers CL, Kantarjian H, et al: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344: 1038-1042, 2001
121. Druker BJ, Talpaz M, Resta DJ, et al: Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344: 1031-1037, 2001
122. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al: Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344: 1052-1056, 2001 123. Druker BJ, Lydon NB: Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 105: 3-7, 2000[Medline] 124. Ergin M, Denning MF, Izban KF, et al: Inhibition of tyrosine kinase activity induces caspase-dependent apoptosis in anaplastic large cell lymphoma with NPM-ALK (p80) fusion protein. Exp Hematol 29: 1082-1090, 2001[CrossRef][Medline] Submitted December 7, 2001; accepted February 14, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
), which encodes a DNA-binding transcription factor. The NPM/RAR
