HnRNP K Is a Haploinsufficient Tumor Suppressor that Regulates Proliferation and Differentiation Programs in Hematologic Malignancies

Miguel Gallardo; Hun Ju Lee; Xiaorui Zhang; Carlos Bueso-Ramos; Laura R. Pageon; Mark McArthur; Asha Multani; Aziz Nazha; Taghi Manshouri; Jan Parker-Thornburg; Inmaculada Rapado; Alfonso Quintas-Cardama; Steven M. Kornblau; Joaquin Martinez-Lopez; Sean M. Post

doi:10.1016/j.ccell.2015.09.001

HnRNP K Is a Haploinsufficient Tumor Suppressor that Regulates Proliferation and Differentiation Programs in Hematologic Malignancies

Miguel Gallardo, Hun Ju Lee, Xiaorui Zhang, Carlos Bueso-Ramos, Laura R. Pageon, Mark McArthur, Asha Multani, Aziz Nazha, Taghi Manshouri, Jan Parker-Thornburg, Inmaculada Rapado, Alfonso Quintas-Cardama, Steven M. Kornblau, Joaquin Martinez-Lopez, Sean M. Post

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

104 Scopus citations

Abstract

hnRNP K regulates cellular programs, and changes in its expression and mutational status have been implicated in neoplastic malignancies. To directly examine its role in tumorigenesis, we generated a mouse model harboring an Hnrnpk knockout allele (Hnrnpk^+/-). Hnrnpk haploinsufficiency resulted in reduced survival, increased tumor formation, genomic instability, and the development of transplantable hematopoietic neoplasms with myeloproliferation. Reduced hnRNP K expression attenuated p21 activation, downregulated C/EBP levels, and activated STAT3 signaling. Additionally, analysis of samples from primary acute myeloid leukemia patients harboring a partial deletion of chromosome 9 revealed a significant decrease in HNRNPK expression. Together, these data implicate hnRNP K in the development of hematological disorders and suggest hnRNP K acts as a tumor suppressor.

Original language	English (US)
Article number	2143
Pages (from-to)	486-499
Number of pages	14
Journal	Cancer cell
Volume	28
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2015.09.001
State	Published - Oct 12 2015

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

MD Anderson CCSG core facilities

Flow Cytometry and Cellular Imaging Facility
Genetically Engineered Mouse Facility
Research Animal Support Facility
Tissue Biospecimen and Pathology Resource

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10.1016/j.ccell.2015.09.001

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Gallardo, M., Lee, H. J., Zhang, X., Bueso-Ramos, C., Pageon, L. R., McArthur, M., Multani, A., Nazha, A., Manshouri, T., Parker-Thornburg, J., Rapado, I., Quintas-Cardama, A., Kornblau, S. M., Martinez-Lopez, J., & Post, S. M. (2015). HnRNP K Is a Haploinsufficient Tumor Suppressor that Regulates Proliferation and Differentiation Programs in Hematologic Malignancies. Cancer cell, 28(4), 486-499. Article 2143. https://doi.org/10.1016/j.ccell.2015.09.001

Gallardo, M, Lee, HJ, Zhang, X, Bueso-Ramos, C, Pageon, LR, McArthur, M, Multani, A, Nazha, A, Manshouri, T, Parker-Thornburg, J, Rapado, I, Quintas-Cardama, A, Kornblau, SM, Martinez-Lopez, J & Post, SM 2015, 'HnRNP K Is a Haploinsufficient Tumor Suppressor that Regulates Proliferation and Differentiation Programs in Hematologic Malignancies', Cancer cell, vol. 28, no. 4, 2143, pp. 486-499. https://doi.org/10.1016/j.ccell.2015.09.001

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title = "HnRNP K Is a Haploinsufficient Tumor Suppressor that Regulates Proliferation and Differentiation Programs in Hematologic Malignancies",

abstract = "hnRNP K regulates cellular programs, and changes in its expression and mutational status have been implicated in neoplastic malignancies. To directly examine its role in tumorigenesis, we generated a mouse model harboring an Hnrnpk knockout allele (Hnrnpk+/-). Hnrnpk haploinsufficiency resulted in reduced survival, increased tumor formation, genomic instability, and the development of transplantable hematopoietic neoplasms with myeloproliferation. Reduced hnRNP K expression attenuated p21 activation, downregulated C/EBP levels, and activated STAT3 signaling. Additionally, analysis of samples from primary acute myeloid leukemia patients harboring a partial deletion of chromosome 9 revealed a significant decrease in HNRNPK expression. Together, these data implicate hnRNP K in the development of hematological disorders and suggest hnRNP K acts as a tumor suppressor.",

author = "Miguel Gallardo and Lee, {Hun Ju} and Xiaorui Zhang and Carlos Bueso-Ramos and Pageon, {Laura R.} and Mark McArthur and Asha Multani and Aziz Nazha and Taghi Manshouri and Jan Parker-Thornburg and Inmaculada Rapado and Alfonso Quintas-Cardama and Kornblau, {Steven M.} and Joaquin Martinez-Lopez and Post, {Sean M.}",

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AU - Pageon, Laura R.

AU - McArthur, Mark

AU - Multani, Asha

AU - Nazha, Aziz

AU - Manshouri, Taghi

AU - Parker-Thornburg, Jan

AU - Rapado, Inmaculada

AU - Quintas-Cardama, Alfonso

AU - Kornblau, Steven M.

AU - Martinez-Lopez, Joaquin

AU - Post, Sean M.

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AB - hnRNP K regulates cellular programs, and changes in its expression and mutational status have been implicated in neoplastic malignancies. To directly examine its role in tumorigenesis, we generated a mouse model harboring an Hnrnpk knockout allele (Hnrnpk+/-). Hnrnpk haploinsufficiency resulted in reduced survival, increased tumor formation, genomic instability, and the development of transplantable hematopoietic neoplasms with myeloproliferation. Reduced hnRNP K expression attenuated p21 activation, downregulated C/EBP levels, and activated STAT3 signaling. Additionally, analysis of samples from primary acute myeloid leukemia patients harboring a partial deletion of chromosome 9 revealed a significant decrease in HNRNPK expression. Together, these data implicate hnRNP K in the development of hematological disorders and suggest hnRNP K acts as a tumor suppressor.

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HnRNP K Is a Haploinsufficient Tumor Suppressor that Regulates Proliferation and Differentiation Programs in Hematologic Malignancies

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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