PBX3 and MEIS1 Cooperate in hematopoietic cells to drive acute myeloid leukemias characterized by a core transcriptome of the MLL-rearranged disease

Zejuan Li; Ping Chen; Rui Su; Chao Hu; Yuanyuan Li; Abdel G. Elkahloun; Zhixiang Zuo; Sandeep Gurbuxani; Stephen Arnovitz; Hengyou Weng; Yungui Wang; Li Shenglai; Hao Huang; Mary Beth Neilly; Gang Greg Wang; Xi Jiang; Paul P. Liu; Jie Jin; Jianjun Chen

doi:10.1158/0008-5472.CAN-15-1566

PBX3 and MEIS1 Cooperate in hematopoietic cells to drive acute myeloid leukemias characterized by a core transcriptome of the MLL-rearranged disease

Zejuan Li, Ping Chen, Rui Su, Chao Hu, Yuanyuan Li, Abdel G. Elkahloun, Zhixiang Zuo, Sandeep Gurbuxani, Stephen Arnovitz, Hengyou Weng, Yungui Wang, Li Shenglai, Hao Huang, Mary Beth Neilly, Gang Greg Wang, Xi Jiang, Paul P. Liu, Jie Jin, Jianjun Chen^*

^*Corresponding author for this work

Obstetrics and Gynecology

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

47 Scopus citations

Abstract

Overexpression of HOXA/MEIS1/PBX3 homeobox genes is the hallmark of mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia (AML). HOXA9 and MEIS1 are considered to be the most critical targets of MLL fusions and their coexpression rapidly induces AML. MEIS1 and PBX3 are not individually able to transform cells and were therefore hypothesized to function as cofactors of HOXA9. However, in this study, we demonstrate that coexpression of PBX3 and MEIS1 (PBX3/MEIS1), without ectopic expression of a HOX gene, is sufficient for transformation of normal mouse hematopoietic stem/progenitor cells in vitro. Moreover, PBX3/MEIS1 overexpression also caused AML in vivo, with a leukemic latency similar to that caused by forced expression of MLL-AF9, the most common form of MLL fusions. Furthermore, gene expression profiling of hematopoietic cells demonstrated that PBX3/ MEIS1 overexpression, but not HOXA9/MEIS1, HOXA9/PBX3, or HOXA9 overexpression, recapitulated the MLL-fusion-mediated core transcriptome, particularly upregulation of the endogenous Hoxa genes. Disruption of the binding between MEIS1 and PBX3 diminished PBX3/MEIS1-mediated cell transformation and HOX gene upregulation. Collectively, our studies strongly implicate the PBX3/MEIS1 interaction as a driver of cell transformation and leukemogenesis, and suggest that this axis may play a critical role in the regulation of the core transcriptional programs activated in MLL-rearranged and HOX-overexpressing AML. Therefore, targeting theMEIS1/PBX3 interaction may represent a promising therapeutic strategy to treat these AML subtypes.

Original language	English (US)
Pages (from-to)	619-629
Number of pages	11
Journal	Cancer Research
Volume	76
Issue number	3
DOIs	https://doi.org/10.1158/0008-5472.CAN-15-1566
State	Published - Feb 1 2016

Funding

The authors thank Drs. Mark P. Kamps, Scott Armstrong, Gregory Hannon, and Lin He for providing retroviral constructs. This work was supported in part by the NIH R01 grants CA178454, CA182528, and CA127277 (J. Chen), Leukemia & Lymphoma Society (LLS) Special Fellowship (Z. Li), LLS Translational ResearchGrant (J. Chen), American Cancer Society (ACS) Research Scholar grant (J. Chen), ACS-IL Research Scholar grant (Z. Li), Gabrielle''s Angel Foundation for Cancer Research (J. Chen, Z. Li, X. Jiang, and H. Huang), and Intramural Research Program of National Human Genome Research Institute, NIH (A.G. Elkahloun and P.P. Liu).

ASJC Scopus subject areas

Oncology
Cancer Research

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Li, Z., Chen, P., Su, R., Hu, C., Li, Y., Elkahloun, A. G., Zuo, Z., Gurbuxani, S., Arnovitz, S., Weng, H., Wang, Y., Shenglai, L., Huang, H., Neilly, M. B., Wang, G. G., Jiang, X., Liu, P. P., Jin, J., & Chen, J. (2016). PBX3 and MEIS1 Cooperate in hematopoietic cells to drive acute myeloid leukemias characterized by a core transcriptome of the MLL-rearranged disease. Cancer Research, 76(3), 619-629. https://doi.org/10.1158/0008-5472.CAN-15-1566

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title = "PBX3 and MEIS1 Cooperate in hematopoietic cells to drive acute myeloid leukemias characterized by a core transcriptome of the MLL-rearranged disease",

abstract = "Overexpression of HOXA/MEIS1/PBX3 homeobox genes is the hallmark of mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia (AML). HOXA9 and MEIS1 are considered to be the most critical targets of MLL fusions and their coexpression rapidly induces AML. MEIS1 and PBX3 are not individually able to transform cells and were therefore hypothesized to function as cofactors of HOXA9. However, in this study, we demonstrate that coexpression of PBX3 and MEIS1 (PBX3/MEIS1), without ectopic expression of a HOX gene, is sufficient for transformation of normal mouse hematopoietic stem/progenitor cells in vitro. Moreover, PBX3/MEIS1 overexpression also caused AML in vivo, with a leukemic latency similar to that caused by forced expression of MLL-AF9, the most common form of MLL fusions. Furthermore, gene expression profiling of hematopoietic cells demonstrated that PBX3/ MEIS1 overexpression, but not HOXA9/MEIS1, HOXA9/PBX3, or HOXA9 overexpression, recapitulated the MLL-fusion-mediated core transcriptome, particularly upregulation of the endogenous Hoxa genes. Disruption of the binding between MEIS1 and PBX3 diminished PBX3/MEIS1-mediated cell transformation and HOX gene upregulation. Collectively, our studies strongly implicate the PBX3/MEIS1 interaction as a driver of cell transformation and leukemogenesis, and suggest that this axis may play a critical role in the regulation of the core transcriptional programs activated in MLL-rearranged and HOX-overexpressing AML. Therefore, targeting theMEIS1/PBX3 interaction may represent a promising therapeutic strategy to treat these AML subtypes.",

author = "Zejuan Li and Ping Chen and Rui Su and Chao Hu and Yuanyuan Li and Elkahloun, {Abdel G.} and Zhixiang Zuo and Sandeep Gurbuxani and Stephen Arnovitz and Hengyou Weng and Yungui Wang and Li Shenglai and Hao Huang and Neilly, {Mary Beth} and Wang, {Gang Greg} and Xi Jiang and Liu, {Paul P.} and Jie Jin and Jianjun Chen",

note = "Publisher Copyright: {\textcopyright} 2016 AACR.",

year = "2016",

month = feb,

day = "1",

doi = "10.1158/0008-5472.CAN-15-1566",

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Li, Z, Chen, P, Su, R, Hu, C, Li, Y, Elkahloun, AG, Zuo, Z, Gurbuxani, S, Arnovitz, S, Weng, H, Wang, Y, Shenglai, L, Huang, H, Neilly, MB, Wang, GG, Jiang, X, Liu, PP, Jin, J & Chen, J 2016, 'PBX3 and MEIS1 Cooperate in hematopoietic cells to drive acute myeloid leukemias characterized by a core transcriptome of the MLL-rearranged disease', Cancer Research, vol. 76, no. 3, pp. 619-629. https://doi.org/10.1158/0008-5472.CAN-15-1566

TY - JOUR

T1 - PBX3 and MEIS1 Cooperate in hematopoietic cells to drive acute myeloid leukemias characterized by a core transcriptome of the MLL-rearranged disease

AU - Li, Zejuan

AU - Chen, Ping

AU - Su, Rui

AU - Hu, Chao

AU - Li, Yuanyuan

AU - Elkahloun, Abdel G.

AU - Zuo, Zhixiang

AU - Gurbuxani, Sandeep

AU - Arnovitz, Stephen

AU - Weng, Hengyou

AU - Wang, Yungui

AU - Shenglai, Li

AU - Huang, Hao

AU - Neilly, Mary Beth

AU - Wang, Gang Greg

AU - Jiang, Xi

AU - Liu, Paul P.

AU - Jin, Jie

AU - Chen, Jianjun

PY - 2016/2/1

Y1 - 2016/2/1

N2 - Overexpression of HOXA/MEIS1/PBX3 homeobox genes is the hallmark of mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia (AML). HOXA9 and MEIS1 are considered to be the most critical targets of MLL fusions and their coexpression rapidly induces AML. MEIS1 and PBX3 are not individually able to transform cells and were therefore hypothesized to function as cofactors of HOXA9. However, in this study, we demonstrate that coexpression of PBX3 and MEIS1 (PBX3/MEIS1), without ectopic expression of a HOX gene, is sufficient for transformation of normal mouse hematopoietic stem/progenitor cells in vitro. Moreover, PBX3/MEIS1 overexpression also caused AML in vivo, with a leukemic latency similar to that caused by forced expression of MLL-AF9, the most common form of MLL fusions. Furthermore, gene expression profiling of hematopoietic cells demonstrated that PBX3/ MEIS1 overexpression, but not HOXA9/MEIS1, HOXA9/PBX3, or HOXA9 overexpression, recapitulated the MLL-fusion-mediated core transcriptome, particularly upregulation of the endogenous Hoxa genes. Disruption of the binding between MEIS1 and PBX3 diminished PBX3/MEIS1-mediated cell transformation and HOX gene upregulation. Collectively, our studies strongly implicate the PBX3/MEIS1 interaction as a driver of cell transformation and leukemogenesis, and suggest that this axis may play a critical role in the regulation of the core transcriptional programs activated in MLL-rearranged and HOX-overexpressing AML. Therefore, targeting theMEIS1/PBX3 interaction may represent a promising therapeutic strategy to treat these AML subtypes.

AB - Overexpression of HOXA/MEIS1/PBX3 homeobox genes is the hallmark of mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia (AML). HOXA9 and MEIS1 are considered to be the most critical targets of MLL fusions and their coexpression rapidly induces AML. MEIS1 and PBX3 are not individually able to transform cells and were therefore hypothesized to function as cofactors of HOXA9. However, in this study, we demonstrate that coexpression of PBX3 and MEIS1 (PBX3/MEIS1), without ectopic expression of a HOX gene, is sufficient for transformation of normal mouse hematopoietic stem/progenitor cells in vitro. Moreover, PBX3/MEIS1 overexpression also caused AML in vivo, with a leukemic latency similar to that caused by forced expression of MLL-AF9, the most common form of MLL fusions. Furthermore, gene expression profiling of hematopoietic cells demonstrated that PBX3/ MEIS1 overexpression, but not HOXA9/MEIS1, HOXA9/PBX3, or HOXA9 overexpression, recapitulated the MLL-fusion-mediated core transcriptome, particularly upregulation of the endogenous Hoxa genes. Disruption of the binding between MEIS1 and PBX3 diminished PBX3/MEIS1-mediated cell transformation and HOX gene upregulation. Collectively, our studies strongly implicate the PBX3/MEIS1 interaction as a driver of cell transformation and leukemogenesis, and suggest that this axis may play a critical role in the regulation of the core transcriptional programs activated in MLL-rearranged and HOX-overexpressing AML. Therefore, targeting theMEIS1/PBX3 interaction may represent a promising therapeutic strategy to treat these AML subtypes.

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PBX3 and MEIS1 Cooperate in hematopoietic cells to drive acute myeloid leukemias characterized by a core transcriptome of the MLL-rearranged disease

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