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

Roberts, K. G., Li, Y., Payne‑Turner, D., Harvey, R. C., Yang, Y.‑L., Pei, D., McCastlain, K., Ding, L., Lu, C., Song, G., Ma, J., Becksfort, J., Rusch, M., Chen, S.‑C., Easton, J., Cheng, J., Boggs, K., Santiago‑Morales, N., Iacobucci, I., Fulton, R. S., Wen, J., Valentine, M., Cheng, C., Paugh, S. W., Devidas, M., Chen, I.‑M., Reshmi, S., Smith, A., Hedlund, E., Gupta, P., Nagahawatte, P., Wu, G., Chen, X., Yergeau, D., Vadodaria, B., Mulder, H., Winick, N. J., Larsen, E. C., Carroll, W. L., Heerema, N. A., Carroll, A. J., Grayson, G., Tasian, S. K., Moore, A. S., Keller, F., Frei‑Jones, M., Whitlock, J. A., Raetz, E. A., White, D. L., Hughes, T. P., Guidry Auvil, J. M., Smith, M. A., Marcucci, G., Bloomfield, C. D., Mrózek, K., Kohlschmidt, J., Stock, W., Kornblau, S. M., Konopleva, M., Paietta, E., Pui, C.‑H., Jeha, S., Relling, M. V., Evans, W. E., Gerhard, D. S., Gastier‑Foster, J. M., Mardis, E., Wilson, R. K., Loh, M. L., Downing, J. R., Hunger, S. P., Willman, C. L., Zhang, J. and Mullighan, C. G. (2014) Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. New England Journal of Medicine, 371 11: 1005-1015. doi:10.1056/NEJMoa1403088

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Author Roberts, K. G.
Li, Y.
Payne‑Turner, D.
Harvey, R. C.
Yang, Y.‑L.
Pei, D.
McCastlain, K.
Ding, L.
Lu, C.
Song, G.
Ma, J.
Becksfort, J.
Rusch, M.
Chen, S.‑C.
Easton, J.
Cheng, J.
Boggs, K.
Santiago‑Morales, N.
Iacobucci, I.
Fulton, R. S.
Wen, J.
Valentine, M.
Cheng, C.
Paugh, S. W.
Devidas, M.
Chen, I.‑M.
Reshmi, S.
Smith, A.
Hedlund, E.
Gupta, P.
Nagahawatte, P.
Wu, G.
Chen, X.
Yergeau, D.
Vadodaria, B.
Mulder, H.
Winick, N. J.
Larsen, E. C.
Carroll, W. L.
Heerema, N. A.
Carroll, A. J.
Grayson, G.
Tasian, S. K.
Moore, A. S.
Keller, F.
Frei‑Jones, M.
Whitlock, J. A.
Raetz, E. A.
White, D. L.
Hughes, T. P.
Guidry Auvil, J. M.
Smith, M. A.
Marcucci, G.
Bloomfield, C. D.
Mrózek, K.
Kohlschmidt, J.
Stock, W.
Kornblau, S. M.
Konopleva, M.
Paietta, E.
Pui, C.‑H.
Jeha, S.
Relling, M. V.
Evans, W. E.
Gerhard, D. S.
Gastier‑Foster, J. M.
Mardis, E.
Wilson, R. K.
Loh, M. L.
Downing, J. R.
Hunger, S. P.
Willman, C. L.
Zhang, J.
Mullighan, C. G.
Title Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia
Journal name New England Journal of Medicine   Check publisher's open access policy
ISSN 0028-4793
Publication date 2014-09-11
Year available 2014
Sub-type Article (original research)
DOI 10.1056/NEJMoa1403088
Open Access Status File (Publisher version)
Volume 371
Issue 11
Start page 1005
End page 1015
Total pages 11
Place of publication Waltham, MA, United States
Publisher Massachusetts Medical Society
Language eng
Subject 2700 Medicine
Formatted 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.)
Keyword Medicine, General & Internal
General & Internal Medicine
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID CA 21765
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Queensland Children's Medical Research Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 332 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 345 times in Scopus Article | Citations
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Created: Thu, 18 Sep 2014, 04:01:42 EST by Andrew Moore on behalf of Child Health Research Centre