Truncating Erythropoietin Receptor Rearrangements in Acute Lymphoblastic Leukemia

Ilaria Iacobucci, Yongjin Li, Kathryn G. Roberts, Stephanie M. Dobson, Jaeseung C. Kim, Debbie Payne-Turner, Richard C. Harvey, Marcus Valentine, Kelly McCastlain, John Easton, Donald Yergeau, Laura J. Janke, Ying Shao, I. Ming L Chen, Michael Rusch, Sasan Zandi, Steven M. Kornblau, Marina Konopleva, Elias Jabbour, Elisabeth M. Paietta & 17 others Jacob M. Rowe, Ching Hon Pui, Julie Gastier-Foster, Zhaohui Gu, Shalini Reshmi, Mignon L. Loh, Janis Racevskis, Martin S. Tallman, Peter H. Wiernik, Mark R Litzow, Cheryl L. Willman, John D. McPherson, James R. Downing, Jinghui Zhang, John E. Dick, Stephen P. Hunger, Charles G. Mullighan

Research output: Contribution to journalArticle

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Abstract

Chromosomal rearrangements are a hallmark of acute lymphoblastic leukemia (ALL) and are important ALL initiating events. We describe four different rearrangements of the erythropoietin receptor gene EPOR in Philadelphia chromosome-like (Ph-like) ALL. All of these rearrangements result in truncation of the cytoplasmic tail of EPOR at residues similar to those mutated in primary familial congenital polycythemia, with preservation of the proximal tyrosine essential for receptor activation and loss of distal regulatory residues. This resulted in deregulated EPOR expression, hypersensitivity to erythropoietin stimulation, and heightened JAK-STAT activation. Expression of truncated EPOR in mouse B cell progenitors induced ALL in vivo. Human leukemic cells with EPOR rearrangements were sensitive to JAK-STAT inhibition, suggesting a therapeutic option in high-risk ALL. Iacobucci et al. show that recurrent EPOR rearrangements occur exclusively in Ph-like acute lymphoblastic leukemia (ALL), resulting in the expression of C-terminal truncated EPOR mutants that have heightened JAK-STAT signaling in response to erythropoietin and confer sensitivity to JAK-STAT inhibition in cases with these rearrangements.

Original languageEnglish (US)
Pages (from-to)186-200
Number of pages15
JournalCancer Cell
Volume29
Issue number2
DOIs
StatePublished - Feb 8 2016

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Erythropoietin Receptors
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Philadelphia Chromosome
Erythropoietin
B-Lymphoid Precursor Cells
Tail
Hypersensitivity
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Iacobucci, I., Li, Y., Roberts, K. G., Dobson, S. M., Kim, J. C., Payne-Turner, D., ... Mullighan, C. G. (2016). Truncating Erythropoietin Receptor Rearrangements in Acute Lymphoblastic Leukemia. Cancer Cell, 29(2), 186-200. https://doi.org/10.1016/j.ccell.2015.12.013

Truncating Erythropoietin Receptor Rearrangements in Acute Lymphoblastic Leukemia. / Iacobucci, Ilaria; Li, Yongjin; Roberts, Kathryn G.; Dobson, Stephanie M.; Kim, Jaeseung C.; Payne-Turner, Debbie; Harvey, Richard C.; Valentine, Marcus; McCastlain, Kelly; Easton, John; Yergeau, Donald; Janke, Laura J.; Shao, Ying; Chen, I. Ming L; Rusch, Michael; Zandi, Sasan; Kornblau, Steven M.; Konopleva, Marina; Jabbour, Elias; Paietta, Elisabeth M.; Rowe, Jacob M.; Pui, Ching Hon; Gastier-Foster, Julie; Gu, Zhaohui; Reshmi, Shalini; Loh, Mignon L.; Racevskis, Janis; Tallman, Martin S.; Wiernik, Peter H.; Litzow, Mark R; Willman, Cheryl L.; McPherson, John D.; Downing, James R.; Zhang, Jinghui; Dick, John E.; Hunger, Stephen P.; Mullighan, Charles G.

In: Cancer Cell, Vol. 29, No. 2, 08.02.2016, p. 186-200.

Research output: Contribution to journalArticle

Iacobucci, I, Li, Y, Roberts, KG, Dobson, SM, Kim, JC, Payne-Turner, D, Harvey, RC, Valentine, M, McCastlain, K, Easton, J, Yergeau, D, Janke, LJ, Shao, Y, Chen, IML, Rusch, M, Zandi, S, Kornblau, SM, Konopleva, M, Jabbour, E, Paietta, EM, Rowe, JM, Pui, CH, Gastier-Foster, J, Gu, Z, Reshmi, S, Loh, ML, Racevskis, J, Tallman, MS, Wiernik, PH, Litzow, MR, Willman, CL, McPherson, JD, Downing, JR, Zhang, J, Dick, JE, Hunger, SP & Mullighan, CG 2016, 'Truncating Erythropoietin Receptor Rearrangements in Acute Lymphoblastic Leukemia', Cancer Cell, vol. 29, no. 2, pp. 186-200. https://doi.org/10.1016/j.ccell.2015.12.013
Iacobucci I, Li Y, Roberts KG, Dobson SM, Kim JC, Payne-Turner D et al. Truncating Erythropoietin Receptor Rearrangements in Acute Lymphoblastic Leukemia. Cancer Cell. 2016 Feb 8;29(2):186-200. https://doi.org/10.1016/j.ccell.2015.12.013
Iacobucci, Ilaria ; Li, Yongjin ; Roberts, Kathryn G. ; Dobson, Stephanie M. ; Kim, Jaeseung C. ; Payne-Turner, Debbie ; Harvey, Richard C. ; Valentine, Marcus ; McCastlain, Kelly ; Easton, John ; Yergeau, Donald ; Janke, Laura J. ; Shao, Ying ; Chen, I. Ming L ; Rusch, Michael ; Zandi, Sasan ; Kornblau, Steven M. ; Konopleva, Marina ; Jabbour, Elias ; Paietta, Elisabeth M. ; Rowe, Jacob M. ; Pui, Ching Hon ; Gastier-Foster, Julie ; Gu, Zhaohui ; Reshmi, Shalini ; Loh, Mignon L. ; Racevskis, Janis ; Tallman, Martin S. ; Wiernik, Peter H. ; Litzow, Mark R ; Willman, Cheryl L. ; McPherson, John D. ; Downing, James R. ; Zhang, Jinghui ; Dick, John E. ; Hunger, Stephen P. ; Mullighan, Charles G. / Truncating Erythropoietin Receptor Rearrangements in Acute Lymphoblastic Leukemia. In: Cancer Cell. 2016 ; Vol. 29, No. 2. pp. 186-200.
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AU - Kim, Jaeseung C.

AU - Payne-Turner, Debbie

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AU - Valentine, Marcus

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AU - Janke, Laura J.

AU - Shao, Ying

AU - Chen, I. Ming L

AU - Rusch, Michael

AU - Zandi, Sasan

AU - Kornblau, Steven M.

AU - Konopleva, Marina

AU - Jabbour, Elias

AU - Paietta, Elisabeth M.

AU - Rowe, Jacob M.

AU - Pui, Ching Hon

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AU - Loh, Mignon L.

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AU - Tallman, Martin S.

AU - Wiernik, Peter H.

AU - Litzow, Mark R

AU - Willman, Cheryl L.

AU - McPherson, John D.

AU - Downing, James R.

AU - Zhang, Jinghui

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AU - Hunger, Stephen P.

AU - Mullighan, Charles G.

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N2 - Chromosomal rearrangements are a hallmark of acute lymphoblastic leukemia (ALL) and are important ALL initiating events. We describe four different rearrangements of the erythropoietin receptor gene EPOR in Philadelphia chromosome-like (Ph-like) ALL. All of these rearrangements result in truncation of the cytoplasmic tail of EPOR at residues similar to those mutated in primary familial congenital polycythemia, with preservation of the proximal tyrosine essential for receptor activation and loss of distal regulatory residues. This resulted in deregulated EPOR expression, hypersensitivity to erythropoietin stimulation, and heightened JAK-STAT activation. Expression of truncated EPOR in mouse B cell progenitors induced ALL in vivo. Human leukemic cells with EPOR rearrangements were sensitive to JAK-STAT inhibition, suggesting a therapeutic option in high-risk ALL. Iacobucci et al. show that recurrent EPOR rearrangements occur exclusively in Ph-like acute lymphoblastic leukemia (ALL), resulting in the expression of C-terminal truncated EPOR mutants that have heightened JAK-STAT signaling in response to erythropoietin and confer sensitivity to JAK-STAT inhibition in cases with these rearrangements.

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