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. Panetta; Sharyn 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

doi:10.1016/j.ccell.2015.07.016

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

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Pages (from-to)	343-356
Number of pages	14
Journal	Cancer cell
Volume	28
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2015.07.016
State	Published - Sep 14 2015

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2015.07.016

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Churchman, M. L., Low, J., Qu, C., Paietta, E. M., Kasper, L. H., Chang, Y., Payne-Turner, D., Althoff, M. J., Song, G., Chen, S. C., Ma, J., Rusch, M., McGoldrick, D., Edmonson, M., Gupta, P., Wang, Y. D., Caufield, W., Freeman, B., Li, L., ... 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

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

@article{691f4684d3d74329b274dd116a20fb4d,

title = "Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = sep,

day = "14",

doi = "10.1016/j.ccell.2015.07.016",

language = "English (US)",

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T1 - Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia

AU - Churchman, Michelle L.

AU - Low, Jonathan

AU - Qu, Chunxu

AU - Paietta, Elisabeth M.

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.

PY - 2015/9/14

Y1 - 2015/9/14

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.

AB - 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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DO - 10.1016/j.ccell.2015.07.016

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AN - SCOPUS:84942371671

SN - 1535-6108

VL - 28

SP - 343

EP - 356

JO - Cancer cell

JF - Cancer cell

IS - 3

ER -

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

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