Loss of p300 accelerates MDS-associated leukemogenesis

G. Cheng, F. Liu, T. Asai, F. Lai, N. Man, H. Xu, S. Chen, S. Greenblatt, P. J. Hamard, K. Ando, X. Chen, Lan Wang, C. Martinez, M. Tadi, L. Wang, M. Xu, F. C. Yang, R. Shiekhattar, S. D. Nimer

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Abstract

The role that changes in DNA methylation and histone modifications have in human malignancies is poorly understood. p300 and CREB-binding protein (CBP), two distinct but highly homologous lysine acetyltransferases, are mutated in several cancers, suggesting their role as tumor suppressors. In the current study, we found that deletion of p300, but not CBP, markedly accelerated the leukemogenesis ofNup98-HoxD13 (NHD13) transgenic mice, an animal model that phenotypically copies human myelodysplastic syndrome (MDS). p300 deletion restored the ability of NHD13 expressing hematopoietic stem and progenitor cells (HSPCs) to self-renew in vitro, and to expand in vivo, with an increase in stem cell symmetric self-renewal divisions and a decrease in apoptosis. Furthermore, loss of p300, but not CBP, promoted cytokine signaling, including enhanced activation of the MAPK and JAK/STAT pathways in the HSPC compartment. Altogether, our data indicate that p300 has a pivotal role in blocking the transformation of MDS to acute myeloid leukemia, a role distinct from that of CBP.Leukemia advance online publication,6 January2017; doi:10.1038/leu.2016.347.

Original languageEnglish (US)
JournalLeukemia
DOIs
StateAccepted/In press - Jan 6 2017

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CREB-Binding Protein
Myelodysplastic Syndromes
Hematopoietic Stem Cells
Histone Code
Neoplasms
Genetically Modified Animals
DNA Methylation
Acute Myeloid Leukemia
Transgenic Mice
Publications
Leukemia
Animal Models
Apoptosis
Cytokines

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Loss of p300 accelerates MDS-associated leukemogenesis. / Cheng, G.; Liu, F.; Asai, T.; Lai, F.; Man, N.; Xu, H.; Chen, S.; Greenblatt, S.; Hamard, P. J.; Ando, K.; Chen, X.; Wang, Lan; Martinez, C.; Tadi, M.; Wang, L.; Xu, M.; Yang, F. C.; Shiekhattar, R.; Nimer, S. D.

In: Leukemia, 06.01.2017.

Research output: Contribution to journalArticle

Cheng, G, Liu, F, Asai, T, Lai, F, Man, N, Xu, H, Chen, S, Greenblatt, S, Hamard, PJ, Ando, K, Chen, X, Wang, L, Martinez, C, Tadi, M, Wang, L, Xu, M, Yang, FC, Shiekhattar, R & Nimer, SD 2017, 'Loss of p300 accelerates MDS-associated leukemogenesis', Leukemia. https://doi.org/10.1038/leu.2016.347
Cheng, G. ; Liu, F. ; Asai, T. ; Lai, F. ; Man, N. ; Xu, H. ; Chen, S. ; Greenblatt, S. ; Hamard, P. J. ; Ando, K. ; Chen, X. ; Wang, Lan ; Martinez, C. ; Tadi, M. ; Wang, L. ; Xu, M. ; Yang, F. C. ; Shiekhattar, R. ; Nimer, S. D. / Loss of p300 accelerates MDS-associated leukemogenesis. In: Leukemia. 2017.
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AU - Martinez, C.

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AU - Xu, M.

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