2017 Fiscal Year Final Research Report
Pathological role of the dysregulated polycomb functions in hematological malignancies
Project/Area Number |
15H02544
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Research Category |
Grant-in-Aid for Scientific Research (A)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Hematology
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Research Institution | Chiba University |
Principal Investigator |
Iwama Atsushi 千葉大学, 大学院医学研究院, 教授 (70244126)
|
Co-Investigator(Kenkyū-buntansha) |
仁田 英里子 神戸大学, 医学研究科, 助教 (80401123)
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Project Period (FY) |
2015-04-01 – 2018-03-31
|
Keywords | 造血腫瘍 / エピジェネティクス / ポリコーム群複合体 |
Outline of Final Research Achievements |
Polycomb-group (PcG) proteins catalyze repressive histone marks. Canonical polycomb repressive complex (PRC) 1 containing Pcgf4/Bmi1 has been implicated in the maintenance of hematopoietic stem cells (HSCs). We analyzed the role of non-canonical PRC1.1 consisting of Pcgf1, Kdm2b, Bcor and Ring1b using conditional knockout mice. We found that PRC1.1 was dispensable for self-renewal capacity of HSCs. Instead, PRC1.1 insufficiency enhanced commitment of hematopoietic stem and progenitor cells (HSPCs) to myeloid lineage and induced myeloid-biased differentiation, eventually leading to the development of lethal myeloproliferative neoplasm (MPN). Comprehensive analyses revealed that master transcriptional factor genes for myeloid differentiation, such as Cebpa, were up-regulated following a reduction in H2AK119ub1 levels in PRC1.1-insufficient HSPCs, resulting in the premature activation of their targets. These results indicate that PRC1.1 negatively regulates myeloid commitment of HSPCs.
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Free Research Field |
血液内科学
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