Hhex Regulates Hematopoietic Stem Cell Self-Renewal and Stress Hematopoiesis via Repression of Cdkn2a

Jacob T. Jackson, Benjamin J. Shields, Wei Shi, Ladina Di Rago, Donald Metcalf, Nicos A Nicola, Matthew P. Mccormack

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)

Abstract

The hematopoietically expressed homeobox transcription factor (Hhex) is important for the maturation of definitive hematopoietic progenitors and B-cells during development. We have recently shown that in adult hematopoiesis, Hhex is dispensable for maintenance of hematopoietic stem cells (HSCs) and myeloid lineages but essential for the commitment of common lymphoid progenitors (CLPs) to lymphoid lineages. Here, we show that during serial bone marrow transplantation, Hhex-deleted HSCs are progressively lost, revealing an intrinsic defect in HSC self-renewal. Moreover, Hhex-deleted mice show markedly impaired hematopoietic recovery following myeloablation, due to a failure of progenitor expansion. In vitro, Hhex-null blast colonies were incapable of replating, implying a specific requirement for Hhex in immature progenitors. Transcriptome analysis of Hhex-null Lin-Sca+Kit+ cells showed that Hhex deletion leads to derepression of polycomb repressive complex 2 (PRC2) and PRC1 target genes, including the Cdkn2a locus encoding the tumor suppressors p16Ink4a and p19Arf. Indeed, loss of Cdkn2a restored the capacity of Hhex-null blast colonies to generate myeloid progenitors in vitro, as well as hematopoietic reconstitution following myeloablation in vivo. Thus, HSCs require Hhex to promote PRC2-mediated Cdkn2a repression to enable continued self-renewal and response to hematopoietic stress.

Original languageEnglish
Pages (from-to)1948-1957
Number of pages10
JournalStem Cells
Volume35
Issue number8
DOIs
Publication statusPublished - Aug 2017

Keywords

  • Cell cycle
  • Hematopoietic stem cells (HSCs)
  • Self-renewal
  • Transcriptional regulation

Cite this

Jackson, Jacob T. ; Shields, Benjamin J. ; Shi, Wei ; Di Rago, Ladina ; Metcalf, Donald ; Nicola, Nicos A ; Mccormack, Matthew P. / Hhex Regulates Hematopoietic Stem Cell Self-Renewal and Stress Hematopoiesis via Repression of Cdkn2a. In: Stem Cells. 2017 ; Vol. 35, No. 8. pp. 1948-1957.
@article{f53014c705f34e7f81212db42bfcd579,
title = "Hhex Regulates Hematopoietic Stem Cell Self-Renewal and Stress Hematopoiesis via Repression of Cdkn2a",
abstract = "The hematopoietically expressed homeobox transcription factor (Hhex) is important for the maturation of definitive hematopoietic progenitors and B-cells during development. We have recently shown that in adult hematopoiesis, Hhex is dispensable for maintenance of hematopoietic stem cells (HSCs) and myeloid lineages but essential for the commitment of common lymphoid progenitors (CLPs) to lymphoid lineages. Here, we show that during serial bone marrow transplantation, Hhex-deleted HSCs are progressively lost, revealing an intrinsic defect in HSC self-renewal. Moreover, Hhex-deleted mice show markedly impaired hematopoietic recovery following myeloablation, due to a failure of progenitor expansion. In vitro, Hhex-null blast colonies were incapable of replating, implying a specific requirement for Hhex in immature progenitors. Transcriptome analysis of Hhex-null Lin-Sca+Kit+ cells showed that Hhex deletion leads to derepression of polycomb repressive complex 2 (PRC2) and PRC1 target genes, including the Cdkn2a locus encoding the tumor suppressors p16Ink4a and p19Arf. Indeed, loss of Cdkn2a restored the capacity of Hhex-null blast colonies to generate myeloid progenitors in vitro, as well as hematopoietic reconstitution following myeloablation in vivo. Thus, HSCs require Hhex to promote PRC2-mediated Cdkn2a repression to enable continued self-renewal and response to hematopoietic stress.",
keywords = "Cell cycle, Hematopoietic stem cells (HSCs), Self-renewal, Transcriptional regulation",
author = "Jackson, {Jacob T.} and Shields, {Benjamin J.} and Wei Shi and {Di Rago}, Ladina and Donald Metcalf and Nicola, {Nicos A} and Mccormack, {Matthew P.}",
year = "2017",
month = "8",
doi = "10.1002/stem.2648",
language = "English",
volume = "35",
pages = "1948--1957",
journal = "Stem Cells",
issn = "1066-5099",
publisher = "AlphaMed Press, Inc",
number = "8",

}

Hhex Regulates Hematopoietic Stem Cell Self-Renewal and Stress Hematopoiesis via Repression of Cdkn2a. / Jackson, Jacob T.; Shields, Benjamin J.; Shi, Wei; Di Rago, Ladina; Metcalf, Donald; Nicola, Nicos A; Mccormack, Matthew P.

In: Stem Cells, Vol. 35, No. 8, 08.2017, p. 1948-1957.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Hhex Regulates Hematopoietic Stem Cell Self-Renewal and Stress Hematopoiesis via Repression of Cdkn2a

AU - Jackson, Jacob T.

AU - Shields, Benjamin J.

AU - Shi, Wei

AU - Di Rago, Ladina

AU - Metcalf, Donald

AU - Nicola, Nicos A

AU - Mccormack, Matthew P.

PY - 2017/8

Y1 - 2017/8

N2 - The hematopoietically expressed homeobox transcription factor (Hhex) is important for the maturation of definitive hematopoietic progenitors and B-cells during development. We have recently shown that in adult hematopoiesis, Hhex is dispensable for maintenance of hematopoietic stem cells (HSCs) and myeloid lineages but essential for the commitment of common lymphoid progenitors (CLPs) to lymphoid lineages. Here, we show that during serial bone marrow transplantation, Hhex-deleted HSCs are progressively lost, revealing an intrinsic defect in HSC self-renewal. Moreover, Hhex-deleted mice show markedly impaired hematopoietic recovery following myeloablation, due to a failure of progenitor expansion. In vitro, Hhex-null blast colonies were incapable of replating, implying a specific requirement for Hhex in immature progenitors. Transcriptome analysis of Hhex-null Lin-Sca+Kit+ cells showed that Hhex deletion leads to derepression of polycomb repressive complex 2 (PRC2) and PRC1 target genes, including the Cdkn2a locus encoding the tumor suppressors p16Ink4a and p19Arf. Indeed, loss of Cdkn2a restored the capacity of Hhex-null blast colonies to generate myeloid progenitors in vitro, as well as hematopoietic reconstitution following myeloablation in vivo. Thus, HSCs require Hhex to promote PRC2-mediated Cdkn2a repression to enable continued self-renewal and response to hematopoietic stress.

AB - The hematopoietically expressed homeobox transcription factor (Hhex) is important for the maturation of definitive hematopoietic progenitors and B-cells during development. We have recently shown that in adult hematopoiesis, Hhex is dispensable for maintenance of hematopoietic stem cells (HSCs) and myeloid lineages but essential for the commitment of common lymphoid progenitors (CLPs) to lymphoid lineages. Here, we show that during serial bone marrow transplantation, Hhex-deleted HSCs are progressively lost, revealing an intrinsic defect in HSC self-renewal. Moreover, Hhex-deleted mice show markedly impaired hematopoietic recovery following myeloablation, due to a failure of progenitor expansion. In vitro, Hhex-null blast colonies were incapable of replating, implying a specific requirement for Hhex in immature progenitors. Transcriptome analysis of Hhex-null Lin-Sca+Kit+ cells showed that Hhex deletion leads to derepression of polycomb repressive complex 2 (PRC2) and PRC1 target genes, including the Cdkn2a locus encoding the tumor suppressors p16Ink4a and p19Arf. Indeed, loss of Cdkn2a restored the capacity of Hhex-null blast colonies to generate myeloid progenitors in vitro, as well as hematopoietic reconstitution following myeloablation in vivo. Thus, HSCs require Hhex to promote PRC2-mediated Cdkn2a repression to enable continued self-renewal and response to hematopoietic stress.

KW - Cell cycle

KW - Hematopoietic stem cells (HSCs)

KW - Self-renewal

KW - Transcriptional regulation

UR - http://www.scopus.com/inward/record.url?scp=85020492785&partnerID=8YFLogxK

U2 - 10.1002/stem.2648

DO - 10.1002/stem.2648

M3 - Article

VL - 35

SP - 1948

EP - 1957

JO - Stem Cells

JF - Stem Cells

SN - 1066-5099

IS - 8

ER -