Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia

Michelle L. Churchman, Jonathan Low, Chunxu Qu, Elisabeth M. Paietta, Lawryn H. Kasper, Yunchao Chang, Debbie Payne-Turner, Mark J. Althoff, Guangchun Song, Shann Ching Chen, Jing Ma, Michael Rusch, Dan McGoldrick, Michael Edmonson, Pankaj Gupta, Yong Dong Wang, William Caufield, Burgess Freeman, Lie Li, John C. PanettaSharyn Baker, Yung Li Yang, Kathryn G. Roberts, Kelly McCastlain, Ilaria Iacobucci, Jennifer L. Peters, Victoria E. Centonze, Faiyaz Notta, Stephanie M. Dobson, Sasan Zandi, John E. Dick, Laura Janke, Junmin Peng, Kiran Kodali, Vishwajeeth Pagala, Jaeki Min, Anand Mayasundari, Richard T. Williams, Cheryl L. Willman, Jacob Rowe, Selina Luger, Ross A. Dickins, R. Kiplin Guy, Taosheng Chen, Charles G. Mullighan

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

Alterations of IKZF1, encoding the lymphoid transcription factor IKAROS, are a hallmark of high-risk acute lymphoblastic leukemia (ALL), however the role of IKZF1 alterations in ALL pathogenesis is poorly understood. Here, we show that in mouse models of BCR-ABL1 leukemia, Ikzf1 and Arf alterations synergistically promote the development of an aggressive lymphoid leukemia. Ikzf1 alterations result in acquisition of stem cell-like features, including self-renewal and increased bone marrow stromal adhesion. Retinoid receptor agonists reversed this phenotype, partly by inducing expression of IKZF1, resulting in abrogation of adhesion and self-renewal, cell cycle arrest, and attenuation of proliferation without direct cytotoxicity. Retinoids potentiated the activity of dasatinib in mouse and human BCR-ABL1 ALL, providing an additional therapeutic option in IKZF1-mutated ALL.

Original languageEnglish (US)
Pages (from-to)343-356
Number of pages14
JournalCancer Cell
Volume28
Issue number3
DOIs
StatePublished - Sep 14 2015

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Retinoids
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Lymphoid Leukemia
Cell Cycle Checkpoints
Leukemia
Transcription Factors
Stem Cells
Bone Marrow
Phenotype
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Churchman, M. L., Low, J., Qu, C., Paietta, E. M., Kasper, L. H., Chang, Y., ... Mullighan, C. G. (2015). Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia. Cancer Cell, 28(3), 343-356. https://doi.org/10.1016/j.ccell.2015.07.016

Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia. / Churchman, Michelle L.; Low, Jonathan; Qu, Chunxu; Paietta, Elisabeth M.; Kasper, Lawryn H.; Chang, Yunchao; Payne-Turner, Debbie; Althoff, Mark J.; Song, Guangchun; Chen, Shann Ching; Ma, Jing; Rusch, Michael; McGoldrick, Dan; Edmonson, Michael; Gupta, Pankaj; Wang, Yong Dong; Caufield, William; Freeman, Burgess; Li, Lie; Panetta, John C.; Baker, Sharyn; Yang, Yung Li; Roberts, Kathryn G.; McCastlain, Kelly; Iacobucci, Ilaria; Peters, Jennifer L.; Centonze, Victoria E.; Notta, Faiyaz; Dobson, Stephanie M.; Zandi, Sasan; Dick, John E.; Janke, Laura; Peng, Junmin; Kodali, Kiran; Pagala, Vishwajeeth; Min, Jaeki; Mayasundari, Anand; Williams, Richard T.; Willman, Cheryl L.; Rowe, Jacob; Luger, Selina; Dickins, Ross A.; Guy, R. Kiplin; Chen, Taosheng; Mullighan, Charles G.

In: Cancer Cell, Vol. 28, No. 3, 14.09.2015, p. 343-356.

Research output: Contribution to journalArticle

Churchman, ML, Low, J, Qu, C, Paietta, EM, Kasper, LH, Chang, Y, Payne-Turner, D, Althoff, MJ, Song, G, Chen, SC, Ma, J, Rusch, M, McGoldrick, D, Edmonson, M, Gupta, P, Wang, YD, Caufield, W, Freeman, B, Li, L, Panetta, JC, Baker, S, Yang, YL, Roberts, KG, McCastlain, K, Iacobucci, I, Peters, JL, Centonze, VE, Notta, F, Dobson, SM, Zandi, S, Dick, JE, Janke, L, Peng, J, Kodali, K, Pagala, V, Min, J, Mayasundari, A, Williams, RT, Willman, CL, Rowe, J, Luger, S, Dickins, RA, Guy, RK, Chen, T & Mullighan, CG 2015, 'Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia', Cancer Cell, vol. 28, no. 3, pp. 343-356. https://doi.org/10.1016/j.ccell.2015.07.016
Churchman, Michelle L. ; Low, Jonathan ; Qu, Chunxu ; Paietta, Elisabeth M. ; Kasper, Lawryn H. ; Chang, Yunchao ; Payne-Turner, Debbie ; Althoff, Mark J. ; Song, Guangchun ; Chen, Shann Ching ; Ma, Jing ; Rusch, Michael ; McGoldrick, Dan ; Edmonson, Michael ; Gupta, Pankaj ; Wang, Yong Dong ; Caufield, William ; Freeman, Burgess ; Li, Lie ; Panetta, John C. ; Baker, Sharyn ; Yang, Yung Li ; Roberts, Kathryn G. ; McCastlain, Kelly ; Iacobucci, Ilaria ; Peters, Jennifer L. ; Centonze, Victoria E. ; Notta, Faiyaz ; Dobson, Stephanie M. ; Zandi, Sasan ; Dick, John E. ; Janke, Laura ; Peng, Junmin ; Kodali, Kiran ; Pagala, Vishwajeeth ; Min, Jaeki ; Mayasundari, Anand ; Williams, Richard T. ; Willman, Cheryl L. ; Rowe, Jacob ; Luger, Selina ; Dickins, Ross A. ; Guy, R. Kiplin ; Chen, Taosheng ; Mullighan, Charles G. / Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia. In: Cancer Cell. 2015 ; Vol. 28, No. 3. pp. 343-356.
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AU - Qu, Chunxu

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AU - Kasper, Lawryn H.

AU - Chang, Yunchao

AU - Payne-Turner, Debbie

AU - Althoff, Mark J.

AU - Song, Guangchun

AU - Chen, Shann Ching

AU - Ma, Jing

AU - Rusch, Michael

AU - McGoldrick, Dan

AU - Edmonson, Michael

AU - Gupta, Pankaj

AU - Wang, Yong Dong

AU - Caufield, William

AU - Freeman, Burgess

AU - Li, Lie

AU - Panetta, John C.

AU - Baker, Sharyn

AU - Yang, Yung Li

AU - Roberts, Kathryn G.

AU - McCastlain, Kelly

AU - Iacobucci, Ilaria

AU - Peters, Jennifer L.

AU - Centonze, Victoria E.

AU - Notta, Faiyaz

AU - Dobson, Stephanie M.

AU - Zandi, Sasan

AU - Dick, John E.

AU - Janke, Laura

AU - Peng, Junmin

AU - Kodali, Kiran

AU - Pagala, Vishwajeeth

AU - Min, Jaeki

AU - Mayasundari, Anand

AU - Williams, Richard T.

AU - Willman, Cheryl L.

AU - Rowe, Jacob

AU - Luger, Selina

AU - Dickins, Ross A.

AU - Guy, R. Kiplin

AU - Chen, Taosheng

AU - Mullighan, Charles G.

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N2 - Alterations of IKZF1, encoding the lymphoid transcription factor IKAROS, are a hallmark of high-risk acute lymphoblastic leukemia (ALL), however the role of IKZF1 alterations in ALL pathogenesis is poorly understood. Here, we show that in mouse models of BCR-ABL1 leukemia, Ikzf1 and Arf alterations synergistically promote the development of an aggressive lymphoid leukemia. Ikzf1 alterations result in acquisition of stem cell-like features, including self-renewal and increased bone marrow stromal adhesion. Retinoid receptor agonists reversed this phenotype, partly by inducing expression of IKZF1, resulting in abrogation of adhesion and self-renewal, cell cycle arrest, and attenuation of proliferation without direct cytotoxicity. Retinoids potentiated the activity of dasatinib in mouse and human BCR-ABL1 ALL, providing an additional therapeutic option in IKZF1-mutated ALL.

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