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

Oncology

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

124 Scopus citations

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
Cell Biology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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{12b76815477b4724a53488422c4ef547,

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 = "Funding Information: We thank K. Georgopolous and S. Nutt for providing Ikzf1 +/− mice and the St. Jude Children{\textquoteright}s Research Hospital Flow Cytometry and Cell Sorting Shared Resource, Cell Tissue and Imaging Center, and Small Animal Imaging Facility. We thank D. Link for discussions regarding Prrx1-Cre; Ai9 mice. This work was supported by the American Lebanese Syrian Associated Charities of St. Jude Children{\textquoteright}s Research hospital, NCI Cancer Center Support Grant P30 CA021765, NCI grant R25 CA23944 (M.J.A.), a Stand Up to Cancer Innovative Research Grant (C.G.M.), the Pew Charitable Trusts (C.G.M.), American Association for Cancer Research/Aflac Career Development Award (C.G.M.), an American Society of Hematology Scholar Award (C.G.M.), and ECOG grants: U10 CA21115 and U24-CA114737. This project has been funded in part with federal funds from the National Cancer Institute, NIH, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = sep,

day = "14",

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

language = "English (US)",

volume = "28",

pages = "343--356",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "3",

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TY - JOUR

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.

N1 - Funding Information: We thank K. Georgopolous and S. Nutt for providing Ikzf1 +/− mice and the St. Jude Children’s Research Hospital Flow Cytometry and Cell Sorting Shared Resource, Cell Tissue and Imaging Center, and Small Animal Imaging Facility. We thank D. Link for discussions regarding Prrx1-Cre; Ai9 mice. This work was supported by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research hospital, NCI Cancer Center Support Grant P30 CA021765, NCI grant R25 CA23944 (M.J.A.), a Stand Up to Cancer Innovative Research Grant (C.G.M.), the Pew Charitable Trusts (C.G.M.), American Association for Cancer Research/Aflac Career Development Award (C.G.M.), an American Society of Hematology Scholar Award (C.G.M.), and ECOG grants: U10 CA21115 and U24-CA114737. This project has been funded in part with federal funds from the National Cancer Institute, NIH, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government. Publisher Copyright: © 2015 Elsevier Inc.

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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JO - Cancer Cell

JF - Cancer Cell

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ER -

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

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