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

K. G. Roberts, Y. Li, D. Payne-Turner, R. C. Harvey, Y. L. Yang, D. Pei, K. McCastlain, L. Ding, C. Lu, G. Song, J. Ma, J. Becksfort, M. Rusch, S. C. Chen, J. Easton, J. Cheng, K. Boggs, N. Santiago-Morales, I. Iacobucci, R. S. Fulton & 54 others J. Wen, M. Valentine, C. Cheng, S. W. Paugh, M. Devidas, I. M. Chen, S. Reshmi, A. Smith, E. Hedlund, P. Gupta, P. Nagahawatte, G. Wu, X. Chen, D. Yergeau, B. Vadodaria, H. Mulder, N. J. Winick, E. C. Larsen, W. L. Carroll, N. A. Heerema, A. J. Carroll, G. Grayson, S. K. Tasian, A. S. Moore, F. Keller, M. Frei-Jones, J. A. Whitlock, E. A. Raetz, D. L. White, T. P. Hughes, J. M. Guidry Auvil, M. A. Smith, G. Marcucci, C. D. Bloomfield, K. Mrózek, J. Kohlschmidt, W. Stock, S. M. Kornblau, M. Konopleva, E. Paietta, C. H. Pui, S. Jeha, M. V. Relling, W. E. Evans, D. S. Gerhard, J. M. Gastier-Foster, E. Mardis, R. K. Wilson, M. L. Loh, J. R. Downing, S. P. Hunger, C. L. Willman, J. Zhang, C. G. Mullighan

Research output: Contribution to journalArticle

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Abstract

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.

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.

Original languageEnglish (US)
Pages (from-to)1005-1015
Number of pages11
JournalNew England Journal of Medicine
Volume371
Issue number11
DOIs
StatePublished - Sep 11 2014

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Philadelphia Chromosome
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Phosphotransferases
Platelet-Derived Growth Factor beta Receptor
Protein-Tyrosine Kinases
B-Lymphoid Precursor Cells
Human Chromosomes
Transcriptome
Heterografts
Young Adult
Leukemia
Transcription Factors
Cytokines
Cell Line
Mutation
Survival

ASJC Scopus subject areas

  • Medicine(all)

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Roberts, K. G., Li, Y., Payne-Turner, D., Harvey, R. C., Yang, Y. L., Pei, D., ... Mullighan, C. G. (2014). Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. New England Journal of Medicine, 371(11), 1005-1015. https://doi.org/10.1056/NEJMoa1403088

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.; Mullighan, C. G.

In: New England Journal of Medicine, Vol. 371, No. 11, 11.09.2014, p. 1005-1015.

Research output: Contribution to journalArticle

Roberts, KG, Li, Y, Payne-Turner, D, Harvey, RC, Yang, YL, Pei, D, McCastlain, K, Ding, L, Lu, C, Song, G, Ma, J, Becksfort, J, Rusch, M, Chen, SC, Easton, J, Cheng, J, Boggs, K, Santiago-Morales, N, Iacobucci, I, Fulton, RS, Wen, J, Valentine, M, Cheng, C, Paugh, SW, Devidas, M, Chen, IM, Reshmi, S, Smith, A, Hedlund, E, Gupta, P, Nagahawatte, P, Wu, G, Chen, X, Yergeau, D, Vadodaria, B, Mulder, H, Winick, NJ, Larsen, EC, Carroll, WL, Heerema, NA, Carroll, AJ, Grayson, G, Tasian, SK, Moore, AS, Keller, F, Frei-Jones, M, Whitlock, JA, Raetz, EA, White, DL, Hughes, TP, Guidry Auvil, JM, Smith, MA, Marcucci, G, Bloomfield, CD, Mrózek, K, Kohlschmidt, J, Stock, W, Kornblau, SM, Konopleva, M, Paietta, E, Pui, CH, Jeha, S, Relling, MV, Evans, WE, Gerhard, DS, Gastier-Foster, JM, Mardis, E, Wilson, RK, Loh, ML, Downing, JR, Hunger, SP, Willman, CL, Zhang, J & Mullighan, CG 2014, 'Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia', New England Journal of Medicine, vol. 371, no. 11, pp. 1005-1015. https://doi.org/10.1056/NEJMoa1403088
Roberts KG, Li Y, Payne-Turner D, Harvey RC, Yang YL, Pei D et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. New England Journal of Medicine. 2014 Sep 11;371(11):1005-1015. https://doi.org/10.1056/NEJMoa1403088
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. / Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. In: New England Journal of Medicine. 2014 ; Vol. 371, No. 11. pp. 1005-1015.
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title = "Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia",
abstract = "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.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.",
author = "Roberts, {K. G.} and Y. Li and D. Payne-Turner and Harvey, {R. C.} and Yang, {Y. L.} and D. Pei and K. McCastlain and L. Ding and C. Lu and G. Song and J. Ma and J. Becksfort and M. Rusch and Chen, {S. C.} and J. Easton and J. Cheng and K. Boggs and N. Santiago-Morales and I. Iacobucci and Fulton, {R. S.} and J. Wen and M. Valentine and C. Cheng and Paugh, {S. W.} and M. Devidas and Chen, {I. M.} and S. Reshmi and A. Smith and E. Hedlund and P. Gupta and P. Nagahawatte and G. Wu and X. Chen and D. Yergeau and B. Vadodaria and H. Mulder and Winick, {N. J.} and Larsen, {E. C.} and Carroll, {W. L.} and Heerema, {N. A.} and Carroll, {A. J.} and G. Grayson and Tasian, {S. K.} and Moore, {A. S.} and F. Keller and M. Frei-Jones and Whitlock, {J. A.} and Raetz, {E. A.} and White, {D. L.} and Hughes, {T. P.} and {Guidry Auvil}, {J. M.} and Smith, {M. A.} and G. Marcucci and Bloomfield, {C. D.} and K. Mr{\'o}zek and J. Kohlschmidt and W. Stock and Kornblau, {S. M.} and M. Konopleva and E. Paietta and Pui, {C. H.} and S. Jeha and Relling, {M. V.} and Evans, {W. E.} and Gerhard, {D. S.} and Gastier-Foster, {J. M.} and E. Mardis and Wilson, {R. K.} and Loh, {M. L.} and Downing, {J. R.} and Hunger, {S. P.} and Willman, {C. L.} and J. Zhang and Mullighan, {C. G.}",
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month = "9",
day = "11",
doi = "10.1056/NEJMoa1403088",
language = "English (US)",
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pages = "1005--1015",
journal = "New England Journal of Medicine",
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TY - JOUR

T1 - Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia

AU - Roberts, K. G.

AU - Li, Y.

AU - Payne-Turner, D.

AU - Harvey, R. C.

AU - Yang, Y. L.

AU - Pei, D.

AU - McCastlain, K.

AU - Ding, L.

AU - Lu, C.

AU - Song, G.

AU - Ma, J.

AU - Becksfort, J.

AU - Rusch, M.

AU - Chen, S. C.

AU - Easton, J.

AU - Cheng, J.

AU - Boggs, K.

AU - Santiago-Morales, N.

AU - Iacobucci, I.

AU - Fulton, R. S.

AU - Wen, J.

AU - Valentine, M.

AU - Cheng, C.

AU - Paugh, S. W.

AU - Devidas, M.

AU - Chen, I. M.

AU - Reshmi, S.

AU - Smith, A.

AU - Hedlund, E.

AU - Gupta, P.

AU - Nagahawatte, P.

AU - Wu, G.

AU - Chen, X.

AU - Yergeau, D.

AU - Vadodaria, B.

AU - Mulder, H.

AU - Winick, N. J.

AU - Larsen, E. C.

AU - Carroll, W. L.

AU - Heerema, N. A.

AU - Carroll, A. J.

AU - Grayson, G.

AU - Tasian, S. K.

AU - Moore, A. S.

AU - Keller, F.

AU - Frei-Jones, M.

AU - Whitlock, J. A.

AU - Raetz, E. A.

AU - White, D. L.

AU - Hughes, T. P.

AU - Guidry Auvil, J. M.

AU - Smith, M. A.

AU - Marcucci, G.

AU - Bloomfield, C. D.

AU - Mrózek, K.

AU - Kohlschmidt, J.

AU - Stock, W.

AU - Kornblau, S. M.

AU - Konopleva, M.

AU - Paietta, E.

AU - Pui, C. H.

AU - Jeha, S.

AU - Relling, M. V.

AU - Evans, W. E.

AU - Gerhard, D. S.

AU - Gastier-Foster, J. M.

AU - Mardis, E.

AU - Wilson, R. K.

AU - Loh, M. L.

AU - Downing, J. R.

AU - Hunger, S. P.

AU - Willman, C. L.

AU - Zhang, J.

AU - Mullighan, C. G.

PY - 2014/9/11

Y1 - 2014/9/11

N2 - 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.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.

AB - 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.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.

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U2 - 10.1056/NEJMoa1403088

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JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

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