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Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia

Kathryn G Roberts¹, Yongjin Li, Debbie Payne-Turner

¹From the Departments of Pathology (K.G.R., D.P.-T., Y.-L.Y., K. McCastlain, G.S., J.M., S.-C.C., J.C., N.S.-M., I.I., J.W., J.R.D., C.G.M.), Computational Biology and Bioinformatics (Y.L., J.B., M.R., E.H., P.G., P.N., G.W., X.C., J.Z.), Biostatistics (D.P., C.C.), Pharmaceutical Sciences (S.W.P., M.V.R., W.E.E.), and Oncology (C.-H.P., S.J.), the Pediatric Cancer Genome Project (Y.L., L.D., C.L., M.R., J.E., J.C., K.B., R.S.F., E.H., P.G., P.N., G.W., X.C., D.Y., B.V., H.M., M.V.R., W.E.E., E.M., R.K.W., J.R.D., J.Z., C.G.M.), and Cytogenetics Shared Resource (M.V.), St. Jude Children's Research Hospital, Memphis, TN; the University of New Mexico Cancer Center and School of Medicine, Albuquerque (R.C.H., I-M.C., C.L.W.); the Genome Institute at Washington University (L.D., C.L., R.S.F., E.M., R.K.W.), the Department of Genetics, Washington University School of Medicine (L.D., C.L., R.S.F., E.M., R.K.W.), and Siteman Cancer Center, Washington University (E.M., R.K.W.) - all in St. Louis; Epidemiology and Health Policy Research, College of Medicine, University of Florida, Gainesville (M.D.); the Research Institute at Nationwide Children's Hospital (S.R., A.S., J.M.G.-F.), the Department of Pathology, College of Medicine, Ohio State University (N.A.H.), and Ohio State University Comprehensive Cancer Center (G.M., C.D.B., K. Mrózek, J.K.) - all in Columbus, OH; the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas (N.J.W.), Scott and White Hospitals and Clinics and Texas A&M Health Science Center, Temple (G.G.), the University of Texas Health Science Center San Antonio, San Antonio (M.F.-J.), and the Departments of Leukemia and Stem Cell Transplantation, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston (S.M.K., M.K.) - all in Texas; Maine Children's Cancer Program, Scarborough (E.C.L.); New York University Cancer Institute, New York (W.L.C.), and the Department of Medicine (Oncology), Albert Einstein

The New England Journal of Medicine

|September 11, 2014

Abstract

Background:

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults.

Methods:

We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL.

Results:

Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6-NTRK3 fusion was sensitive to crizotinib.

Conclusions:

Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. (Funded by the American Lebanese Syrian Associated Charities and others.).

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