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Pathogenesis of Myelofibrosis With Myeloid Metaplasia

From the Division of Hematology, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN

Address reprint requests to Ayalew Tefferi, MD, Division of Hematology, Department of Internal Medicine, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905; e-mail: tefferi.ayalew{at}mayo.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION CLONALITY STUDIES THE SEARCH FOR DISEASE-SPECIFIC... PATHOGENETIC MECHANISM OF BONE... THERAPEUTIC IMPLICATIONS Author's Disclosures of... REFERENCES

 
The primary disease process in myelofibrosis with myeloid metaplasia (MMM) is clonal myeloproliferation with varying degrees of phenotypic differentiation. This is characteristically accompanied by secondary intramedullary collagen fibrosis, osteosclerosis, angiogenesis, and extramedullary hematopoiesis. Modern clonality studies have confirmed the multipotent stem-cell origin of the neoplastic process in MMM. The nature of the specific oncogenic mutation(s) is currently being unraveled with the recent discovery of an association between a somatic point mutation of JAK2 tyrosine kinase (V617F) and bcr/abl-negative myeloproliferative disorders, including MMM. The pathogenetic mechanisms that underlie the secondary bone marrow stromal changes in MMM are also incompletely understood. Mouse models of this latter disease aspect have been constructed by either in vivo overexpression of thrombopoietin (TPO^high mice) or megakaryocyte lineage restricted underexpression of the transcription factor GATA-1 (GATA-1^low mice). Gene knockout experiments using such animal models have suggested the essential role of hematopoietic cell-derived transforming growth factor beta1 in inducing bone marrow fibrosis and stromal cell–derived osteoprotegerin in promoting osteosclerosis. However, experimental myelofibrosis in mice does not recapitulate clonal myeloproliferation that is fundamental to human MMM. Other cytokines that are implicated in mediating myelofibrosis and angiogenesis in MMM include basic fibroblast, platelet-derived, and vascular endothelial growth factors. It is currently assumed that such cytokines are abnormally released from clonal megakaryocytes as a result of a pathologic interaction with neutrophils (eg, emperipolesis). This latter phenomenon, through neutrophil-derived elastase, could also underlie the abnormal peripheral-blood egress of myeloid progenitors in MMM.

	INTRODUCTION

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Myelofibrosis with myeloid metaplasia (MMM) was first described in 1879¹ and is currently classified as a myeloproliferative disorder (MPD).² The disease presents either de novo (agnogenic myeloid metaplasia) or in the setting of both polycythemia vera (PV; postpolycythemic myeloid metaplasia) and essential thrombocythemia (ET; post-thrombocythemic myeloid metaplasia).^3,4 The clinical phenotype includes progressive anemia, massive splenomegaly, a leukoerythroblastic blood smear, profound constitutional symptoms, cachexia, and hepatosplenic as well as nonhepatosplenic extramedullary hematopoiesis.⁵ Bone marrow histology displays substantial collagen fibrosis, osteosclerosis, and angiogenesis.⁶ Most patients are diagnosed after age 60 years,⁷ and reported median survival ranges from 3.5 to 10 years.^8-11 Causes of death include infection, bleeding, organ failure, portal hypertension, and leukemic transformation.^9-11 The latter occurs in 8% to 23% of the patients in the first decade of the disease. Current drug therapy has not altered the natural history of the disease.¹² Although the prospect of cure is possible with allogeneic hematopoietic stem-cell transplantation, the majority of affected patients are not suitable candidates for the particular treatment modality because of either advanced age or the presence of comorbid conditions.¹³ Therefore, rational treatment approaches in MMM await elucidation of the underlying pathogenetic mechanisms of both clonal myeloproliferation¹⁴ and the reactive bone marrow stromal changes that are believed to be cytokine mediated.¹⁵

	CLONALITY STUDIES

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Normal hematopoiesis in large animals is polyclonal, and individual multipotent stem cells are capable of both myeloid and lymphoid lineage differentiation.¹⁶ In contrast, hematopoiesis in patients with MPD, including those with MMM, is monoclonal and is supported by a genetically transformed mutant clone that retains the capacity to differentiate across multiple cell lineages.¹⁷ In general, clonality studies in MPD have mostly been based on allelic polymorphisms between the paternally and maternally derived X chromosomes in females.¹⁸ In a normal (polyclonal) somatic cell population, the random X chromosome inactivation process has affected both the maternal and paternal X chromosomes.¹⁹ In a clonal cell population, in contrast, because of the single-cell derivation of the neoplastic process, only the maternal or the paternal X chromosome is affected (not both). This difference in X chromosome inactivation pattern between so-called normal and clonal cell populations can be demonstrated in informative (heterozygous at the genetic locus of interest) females, at either the DNA (on the basis of methylation differences between active and inactive genes),²⁰ or post-DNA level (on the basis of the fact that RNA and enzyme expression is restricted to the active chromosome).^18,21,22 Some of the classic studies in this regard have used glucose-6-phosphate dehydrogenase isoenzyme analysis (ie, protein level investigation),^14,23,24 whereas more recent studies have focused on X-linked DNA^25,26 and transcript²¹ analysis.

Monoclonality in MMM was suggested as early as 1968 based on the clonal occurrence of an abnormal chromosome marker.²⁷ Subsequent glucose-6-phosphate dehydrogenase–based clonality studies in the 1970s documented clonal involvement of bone marrow mononuclear cells as well as peripheral-blood granulocytes, erythrocytes, and platelets, but not bone marrow fibroblasts.^14,28 Similarly, X-linked DNA analysis has revealed monoclonal X chromosome inactivation pattern in peripheral-blood leukocytes,²⁹ granulocytes,^26,30 bone marrow mononuclear cells,²⁶ and, in some cases, T lymphocytes.³⁰ These observations were supported by cytogenetics-based demonstration of clonality in erythroid,^31,32 granulocyte-monocyte,^31,32 and granulocyte-monocyte-erythroid progenitors,³² but not in fibroblasts.^33,34 Clonality in MMM has also been investigated using N-ras mutation as a marker and showing its presence in granulocytes, monocytes, and erythroblasts, as well as B and T lymphocytes.³⁵ Similarly, a recent study used a combination of immunomagnetic cell separation technique and interphase cytogenetics to demonstrate clonal involvement of T and B lymphocytes (Fig 1). ¹⁷ Therefore, current evidence strongly supports the true stem-cell nature of the mutant clone in MMM, and within the confines of the available testing methods, interpatient heterogeneity in the extent of clonal involvement by a specific cell type has been demonstrated.^17,30

View larger version (40K): [in this window] [in a new window]   Fig 1. Fluorescent in situ hybridization studies of T (CD3+) and B (CD19+) lymphocytes, neutrophils, and precursor cells of myeloid (CD34+), megakaryocyte (CD61+), and erythroid (CD71+) lineage in myelofibrosis with myeloid metaplasia. All cells exhibit a single orange signal, revealing a deletion of the long arm of chromosome 20/13, and two green signals of the control probe.

	THE SEARCH FOR DISEASE-SPECIFIC MUTATIONS

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View larger version (38K): [in this window] [in a new window]   Fig 2. Karyotypic abnormalities (Abns) in 83 chemotherapy-naive patients with myelofibrosis with myeloid metaplasia. For comparison, the prevalence of each anomaly in other chronic myeloid disorders, including polycythemia vera (PV), essential thrombocythemia (ET), and myelodysplastic syndrome (MDS), is provided in the box below the figure.63,199-201.

Mutation Screening Studies
The pathogenesis of MMM and related bcr/abl-negative MPD might be explained, in part, by a somatic point mutation on exon 14 (V617F) of the JAK2 kinase gene that is located on chromosome 9p24.^71-73 The recurrent JAK2 mutation was identified by either a candidate gene approach^71,73 or a high-throughput DNA sequencing of the functional domains of 85 human tyrosine kinases.⁷² The incidence of the mutant allele in granulocytes collected from MPD patients was 35% to 50% in MMM, 32% to 57% in ET, and 74% to 97% in PV.^72,73 No mutation was detected in either normal individuals or patients with secondary erythrocytosis.^71-73 The JAK2 V617F mutation occurs within the auto-inhibitory JH2 domain, resulting in dysregulation of kinase activity that resides in the JH1 domain. Supporting evidence for this comes from the demonstration of mutant allele-mediated activation of both JAK2- and STAT5-mediated transcription, as well as the induction of either Epo hypersensitivity or growth factor independence in cell lines.^71,72 Furthermore, erythrocytosis was induced in mice transplanted with bone marrow cells carrying the mutant allele.⁷¹ However, direct mutation screening for other candidate genes, including type III receptor tyrosine kinases (c-kit, c-fms, flt-3), has generally yielded negative results.^74,75

Loss-of-Heterozygosity Studies
In certain human cancers, loss of heterozygosity (LOH) of chromosomal regions harboring mutated tumor suppressor genes is either a key oncogenic event or contributes to disease progression. Genome-wide patterns of LOH can be studied using polymorphic genetic markers, and the principle behind the particular molecular investigation is that the loss of the normal allele of a tumor suppressor gene in the presence of a mutated allele results in homozygous loss of protective gene function.⁷⁶

In a recent study, a genome-wide screening for LOH using 86 polymorphic markers encompassing all 22 autosomes was performed on CD34⁺ cells obtained from 29 patients with MMM.⁷⁷ Allelic loss was compared with that of normal T lymphocytes from the same patients. After combing the results of marker studies on the same arm of individual chromosomes, the most frequent allelic loss was observed on 1q (25%), 3p (24%), and 3q (22%).⁷⁷ Interestingly, the LOH patterns were not correlated with structural lesions detected by cytogenetic studies. Using 23 additional LOH markers, a detailed mapping of the chromosome 3p arm between D3S1597 and D3S1578 revealed a CDR between D3S1583 and D3S1609 at 3p24 that houses the retinoic acid receptor tumor suppressor gene. Subsequent experiments revealed that RAR2 gene expression was markedly decreased in all tested patients with MMM, even in the absence of LOH at the particular locus. Additional experiments suggested that this was the result of an epigenetic mechanism mediated by abnormal methylation of the gene promoter P2.⁷⁷ Although RAR is considered important in myeloid differentiation, additional studies are needed to decipher the specific pathogenetic role of the observed phenomenon in MMM. In the meantime, the particular work provides support for evaluating the therapeutic value of demethylating as well as retinoic acid-based agents in MMM.^78,79

Gene Expression Studies
In gene expression analysis, an altered gene or biochemical pathway associated with a particular disease may be revealed by the identification of a consistently upregulated or downregulated gene across a cohort of patients with the same disease.⁸⁰ Global gene expression profiling has been shown to accurately distinguish among previously established phenotypic categories of hematologic malignancies as well as reveal additional molecular classes.⁸¹ More importantly, considerable pathogenetic insight may be obtained by comparing gene expression patterns of diseased and normal tissue.

To date, only one study has evaluated MMM by oligonucleotide microarray analysis.⁸² Gene expression by CD34⁺ cells in eight patients with MMM was compared with that of six normal controls. Upregulated genes in MMM included several transcription factors (JUNB at 19p13.2, GATA2 at 3q21, N-myc at 2p24.1), granulocyte-macrophage colony-stimulating factor (CSF1 at 5q33), interleukin-8 (IL8 at 4q13-21), IL1B at 2q14, platelet-derived endothelial cell growth factor (PDECGF at 22q13.33), platelet factor 4 at 4q12-21, and delta, Drosophila homolog-like 1 (DLK1 at 14q32). Downregulated genes included connective tissue growth factor (CTGF) that is located on chromosome 6q23.1, osteopontin (OPN) located at 4q21-25, FK-506 binding protein 5 (FKBP5) located at 6p21, bone morphogenic protein 2B (BMP2B) located at 14q22-23, macrophage inhibitory cytokine-1 (MIC-1) located at 19p13, BCL-1 located at 11q13, cell division cycle 2 (cdc2) located 10q21.1, and cdc20 located at 9q13-21.

Some of the upregulated transcription factors (eg, N-myc) may be relevant to cell cycle progression and, along with some of the overexpressed growth factors (eg, CSF1, PDECGF) and pleiotropic cytokines (eg, IL-8, IL-1B), might contribute to the myeloproliferation and stromal reaction in MMM.^83-85 Dlk1 is a transmembrane protein belonging to the superfamily of epidermal growth factor–like proteins and is essential for normal hematopoiesis, and its abnormal expression has also been demonstrated in myelodysplastic syndrome.⁸⁶ Osteopontin is a secreted cell attachment phosphoprotein that might participate in cell-matrix interaction and might facilitate fibroblast, osteoblast, and osteoclast contribution to the pathology of the stromal reaction in MMM.⁸⁷ BMP2B might play a similar role in the associated changes in bone remodeling.⁸⁸ The results of the aforementioned DNA microarray study regarding FKBP51 gene expression is at odds with another study that used a differential display approach and demonstrated overexpression in megakaryocytes derived from CD34⁺ cells of patients with MMM.⁷⁰ The discrepancy might have arisen from either the distinct cell populations studied in the two different reports (peripheral-blood CD34⁺ cells⁸² v CD34-derived megakaryocytes⁷⁰) or the associated experimental conditions in the latter study (comparison of cytokine-prepared normal megakaryocytes v spontaneously grown MMM megakaryocytes).⁷⁰ Regardless, the systematic evaluation of data coming out of various types of gene expression studies, including DNA microarray analysis, should help generate specific hypothesis for more focused molecular investigations.

Other Molecular and Biologic Studies
Another biologic feature of megakaryocytes in MMM is their endogenous (cytokine-independent) growth capability as well as their hypersensitivity to various growth factors, including thrombopoietin (TPO).^89-94 The specific in vitro growth characteristic might also affect other cell lineages^95,96 and is not specific to MMM, as it is readily seen in other MPD, including PV^97-99 and ET.^96,100-102 Such growth factor independence is not seen in either normal subjects or reactive myeloproliferation¹⁰³ and, in MPD, has not been attributed to mutations in ligand receptor^89,104 or receptor-associated signal transducer molecules.¹⁰⁵ One suggested mechanism of intrinsic growth factor hypersensitivity in MMM involves megakaryocyte overexpression of FKBP51 that is associated with constitutive JAK2/STAT5 activation.^70,106 This possibility is consistent with the recent discovery of an activation mutation of JAK2 (V617F) in MPD.^71-73 However, megakaryocyte FKBP51 gene as well as protein expression in MMM was shown to be similar to that of normal megakaryocytes in another study.¹⁰⁷

Another study has suggested the constitutive activation of the c/JAK3/STAT3 pathway in CD34⁺ cells from patients with MMM that was coupled with the inability to differentiate into natural-killer cells.¹⁰⁸ Obviously, such examples of altered cellular biology are by no means specific to MMM and could represent a nonspecific feature that is common to many neoplastic cell processes.^109,110 The same can be said about the stem-cell leukemia gene, the expression of which in blood mononuclear cells from patients with MMM was shown to be increased.¹¹¹ Markedly decreased megakaryocyte/platelet expression of the TPO receptor (Mpl) is another nonspecific^112,113 cellular feature in MMM¹¹⁴ that is also seen in ET¹¹⁵ and PV.¹¹⁴ The particular phenomenon has been blamed for the normal or elevated serum concentrations of TPO in MMM¹¹⁶ that is unexpected in lieu of the disease-associated increased megakaryocyte mass.

	PATHOGENETIC MECHANISM OF BONE MARROW STROMAL REACTION

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MMM is typically characterized by bone marrow collagen fibrosis, new bone formation (osteosclerosis), and angiogenesis.^6,117 As elaborated in the previous section on clonality studies, bone marrow fibroblasts in MMM are polyclonal^33,34,118 and exhibit normal function and in vitro growth characteristics.¹¹⁸ This information, coupled with the observation that both cellular and extracellular levels of various fibrogenic and angiogenic cytokines are altered in patients with MMM, strongly supports the contention that the bone marrow histologic changes in MMM are reactive and cytokine mediated.^118-120 In this regard, several patient-centered studies have suggested a pathogenetic role for transforming growth factor beta (TGF-ß),^121-123 platelet-derived growth factor,¹²³ basic fibroblast growth factor,^124-126 vascular endothelial growth factor (VEGF),¹²⁷ and tissue inhibitors of matrix metalloproteinases.^128,129 Similar circumstantial evidence has long suggested that megakaryocytes^122,130 and activated monocytes¹²⁰ might be the source of the aforementioned nosogenic cytokines. Furthermore, a pathologic interaction between megakaryocytes and neutrophils (emperipolesis), induced by altered megakaryocyte P-selectin distribution, might underlie the abnormal cytokine release mechanism.^131,132 Neutrophil-derived enzymes, including elastase, might also participate in the pathologic process by facilitating peripheral-blood egress of myeloid progenitors.^133-135

Mouse models of myelofibrosis have provided additional information regarding the role of certain cytokines in the pathogenesis of the stromal reaction in MMM.^136,137 There are currently two established models of experimental myelofibrosis in mice: TPO^high and GATA-1^low mice. The former is constructed by the systemic overexpression of thrombopoietin^137-140 and the latter by megakaryocyte lineage restricted underexpression of the transcription factor GATA-1.¹⁴¹ The common feature to both experimental models is tissue accumulation of megakaryocytes, a result of TPO-driven proliferation in TPO^high mice¹⁴² and impaired megakaryocyte maturation in GATA-1^low mice.¹⁴³ However, considerable heterogeneity exists among different mouse models in terms of both phenotype and disease tempo (Fig 3). ^{138,140,141,144-146} In immune-deficient mice, myelofibrosis and osteosclerosis developed only in the severe combined immunodeficient (T and B cell deficient) model attributed to both the high degree of TPO expression, compared with the nude (T cell deficient) model, as well as the retention of intact monocyte-macrophage function, compared with the nonobese diabetic severe combined immunodeficient (T and B as well as multiple other defects in innate immunity, including NK and monocyte-macrophage function) model.^146,147 Furthermore, experimental myelofibrosis in TPO^high mice has been shown to be reversible either by transplantation¹³⁹ or cessation of the systemic administration of TPO.¹⁴⁸

View larger version (70K): [in this window] [in a new window]   Fig 3. Mouse models of myelofibrosis. Transgenic GATA-1low or IgH/mTPOhigh develop a complete myelofibrosis with myeloid metaplasia phenotype with delayed onset of myelofibrosis and osteosclerosis.141,145 In contrast, transgenic ApoE/hTPOhigh mice develop incomplete phenotype, megakaryocytic hyperplasia without myelofibrosis.144 Similarly, both complete138,140,146 and incomplete146 phenotypes are seen in nontransgenic mouse models whose bone marrow stem cells were retrovirally transduced to overexpress thrombopoietin. SCID, severe combined immunodeficient disease; NOD-SCID, nonobese diabetic severe combined immunodeficient disease.

	THERAPEUTIC IMPLICATIONS

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The aforementioned pathogenetic information regarding the stromal reaction in MMM underlies the rationale for testing a series of drugs at my institution over the last 12 years. Accordingly, specific drugs that have been evaluated included those that were directed at reducing megakaryocyte bulk (interferon alfa-2a,¹⁵³ cladribine^154,155), impairing megakaryocyte differentiation and thus possibly interfering with megakaryocyte-neutrophil interaction (anagrelide¹⁵⁶), inhibiting TGF-ß–mediated fibroblast proliferation and collagen synthesis (suramin,¹⁵⁷ pirfenidone¹⁵⁸), inhibiting platelet-derived growth factor receptor–associated tyrosine kinase activity (imatinib mesylate¹⁵⁹), and interfering with angiogenesis and TNF- production (thalidomide,^160-163 etanercept¹⁶⁴). Unfortunately, none of these agents were shown to induce favorable changes in bone marrow stroma, although clinical benefit was demonstrated with cladribine, thalidomide, and etanercept.^155,160,164 On the basis of these findings, we are currently running treatment trials with a more potent thalidomide analog (CC-5013; lenalidomide; Revlimid; Celgene, Summit, NJ) as well as combination therapy with thalidomide and etanercept. Revlimid is the lead compound among the immunomodulatory analogs of thalidomide (ImiDs), and its ex vivo antiangiogenic as well as anti-tumor necrosis factor property is estimated to be at least 50-fold higher than that of thalidomide.^165,166 Within the context of myeloid malignancies, the drug was recently shown to have excellent therapeutic activity in MDS associated with a 5q- chromosomal abnormality.¹⁶⁷

There are several other antiangiogenic agents that might be considered for future therapeutic trials in MMM. In this regard, we have recently completed a phase II study (unpublished) with a farnesyl transferase inhibitor (R115777) that is known to downregulate VEGF expression.¹⁶⁸ Some promise of therapeutic activity in this regard has already been communicated by other investigators.¹⁶⁹ In another upcoming pilot study, we plan to evaluate the therapeutic activity of bortezomib,¹⁷⁰ a proteosome inhibitor, which in addition to its indirect antiangiogenic effect, might overcome the antiapoptotic effect of FKBP51 overexpression in MMM.^70,106 Other antiangiogenic agents that are undergoing clinical trials and are potent inhibitors of VEGF receptors, platelet-derived growth factor receptor, and Kit include SU-5416, SU-6668, and PTK-787.^171-173 In general, these agents were well tolerated, but their activity has so far been underwhelming.^171,173 Rapamycin is another antiangiogenic drug¹⁷⁴ that might be worth looking into because it also interferes with collagen synthesis¹⁷⁵ and abnormal granulocyte migration.^135,176

Another venue of therapeutic trials might target the downstream effectors of TGF-ß.¹⁷⁷ One such candidate molecule is connective tissue growth factor,^178,179 and human monoclonal antibodies against connective tissue growth factor are already being evaluated in clinical trials involving other fibrotic disorders.¹⁸⁰ One can also envision treatment molecules that target either the TGF-ß receptor^181,182 or the postreceptor signaling intermediates, the Smad proteins.^183,184 In the end, it is likely that a combination of drugs directed at different molecules might be needed for effective control of the composite stromal aberration in MMM. In this regard, the recently discovered, MPD-associated JAK2 V617F might constitute a molecular target for the development of rational drug therapy.¹⁸⁵

In summary, based on the composite set of information obtained from laboratory investigation of patient samples as well as experimental myelofibrosis in mice, a working model of the stromal reaction in MMM is proposed (Fig 4). In this model, the central event is the accumulation of bone marrow megakaryocytes that is clonal¹⁷ in man but cytokine-mediated in experimental myelofibrosis.^137-141 These megakaryocytes, both in man and mice, are also qualitatively abnormal and exhibit abnormal distribution of P-selectin^131,132 and decreased expression of Mpl.¹¹⁴ The former abnormality promotes a pathologic interaction with neutrophils (emperipolesis) and the latter an in situ increase in TPO concentration. The excess TPO might enhance the underlying clonal myeloproliferation as well as induce stromal cells to produce fibrogenic, osteogenic, and angiogenic cytokines. Such cytokines are also abnormally released as a result of the aforementioned emperipolesis as well as activation of clonal monocytes.¹²⁰ The different components of the overall stromal reaction (fibrosis, osteosclerosis, angiogenesis, CD34 cell egress) might be linked to one or more specific cytokines.^136,150

View larger version (71K): [in this window] [in a new window]   Fig 4. A working model for the pathogenesis of myelofibrosis with myeloid metaplasia. In both the human disease and experimental myelofibrosis in mice, a pathologic interaction between the quantitatively as well as biologically altered megakaryocytes and neutrophils results in abnormal release of fibrogenic and angiogenic cytokines that mediate the bone marrow stromal reaction. TGF-ß, transforming growth factor beta; PDGF, platelet-derived growth factor; bFGF, basic fibroblast growth factor; OPG, osteoprotegerin.

	Author's Disclosures of Potential Conflicts of Interest

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The author indicated no potential conflicts of interest.

	NOTES

 
Author's disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION CLONALITY STUDIES THE SEARCH FOR DISEASE-SPECIFIC... PATHOGENETIC MECHANISM OF BONE... THERAPEUTIC IMPLICATIONS Author's Disclosures of... REFERENCES

 
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Submitted December 13, 2004; accepted March 24, 2005.

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