Originally published as JCO Early Release 10.1200/JCO.2006.09.3534 on February 20 2007

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Differential Gene Expression Patterns and Interaction Networks in BCR-ABL–Positive and –Negative Adult Acute Lymphoblastic Leukemias

Dejan Juric, Norman J. Lacayo, Meghan C. Ramsey, Janis Racevskis, Peter H. Wiernik, Jacob M. Rowe, Anthony H. Goldstone, Peter J. O'Dwyer, Elisabeth Paietta, Branimir I. Sikic

From the Divisions of Medical Oncology and Pediatric Hematology/Oncology, Stanford University School of Medicine, Stanford, CA; Our Lady of Mercy Cancer Center, New York Medical College, Bronx, NY; Hematology Department, Rambam Medical Center, Haifa, Israel; University College London Hospitals, London, United Kingdom; Division of Hematology-Oncology and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; and the Eastern Cooperative Oncology Group, Boston, MA

Address reprint requests to Branimir I. Sikic, MD, Oncology Division, Department of Medicine, Stanford University School of Medicine, CCSR 1105, 269 Campus Dr, Stanford, CA 94305-5151; e-mail: brandy{at}stanford.edu

Purpose To identify gene expression patterns and interaction networks related to BCR-ABL status and clinical outcome in adults with acute lymphoblastic leukemia (ALL).

Patients and Methods DNA microarrays were used to profile a set of 54 adult ALL specimens from the Medical Research Council UKALL XII/Eastern Cooperative Oncology Group E2993 trial (21 p185^BCR-ABL–positive, 16 p210^BCR-ABL–positive and 17 BCR-ABL–negative specimens).

Results Using supervised and unsupervised analysis tools, we detected significant transcriptomic changes in BCR-ABL–positive versus –negative specimens, and assessed their validity in an independent cohort of 128 adult ALL specimens. This set of 271 differentially expressed genes (including GAB1, CIITA, XBP1, CD83, SERPINB9, PTP4A3, NOV, LOX, CTNND1, BAALC, and RAB21) is enriched for genes involved in cell death, cellular growth and proliferation, and hematologic system development and function. Network analysis demonstrated complex interaction patterns of these genes, and identified FYN and IL15 as the hubs of the top-scoring network. Within the BCR-ABL–positive subgroups, we identified genes overexpressed (PILRB, STS-1, SPRY1) or underexpressed (TSPAN16, ADAMTSL4) in p185^BCR-ABL–positive ALL relative to p210^BCR-ABL–positive ALL. Finally, we constructed a gene expression- and interaction-based outcome predictor consisting of 27 genes (including GRB2, GAB1, GLI1, IRS1, RUNX2, and SPP1), which correlated with overall survival in BCR-ABL–positive adult ALL (P = .0001), independent of age (P = .25) and WBC count at presentation (P = .003).

Conclusion We identified prominent molecular features of BCR-ABL–positive adult ALL, which may be useful for developing novel therapeutic targets and prognostic markers in this disease.

published online ahead of print at www.jco.org on February 20, 2007.

Supported by United States Public Health Service Grant No. CA 21115 to the Eastern Cooperative Oncology Group, and by the Sikic Laboratory Research Fund.

E.P. and B.I.S. contributed equally to this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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