Requirement for Ssbp2 in hematopoietic stem cell maintenance and stress response

June Li, Yasuhiro Kurasawa, Yang Wang, Karen Clise-Dwyer, Sherry A. Klumpp, Hong Liang, Ramesh C. Tailor, Aaron C. Raymond, Zeev Estrov, Stephen J. Brandt, Richard E. Davis, Patrick Zweidler-McKay, Hesham M. Amin, Lalitha Nagarajan

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Transcriptional mechanisms governing hematopoietic stem cell (HSC) quiescence, self-renewal, and differentiation are not fully understood. Sequence-specific ssDNA-binding protein 2 (SSBP2) is a candidate acute myelogenous leukemia (AML) suppressor gene located at chromosome 5q14. SSBP2 binds the transcriptional adaptor protein Lim domain-binding protein 1 (LDB1) and enhances LDB1 stability to regulate gene expression. Notably, Ldb1 is essential for HSC specification during early development and maintenance in adults. We previously reported shortened lifespan and greater susceptibility to B cell lymphomas and carcinomas in Ssbp2-/- mice. However, whether Ssbp2 plays a regulatory role in normal HSC function and leukemogenesis is unknown. In this study, we provide several lines of evidence to demonstrate a requirement for Ssbp2 in the function and transcriptional program of hematopoietic stem and progenitor cells (HSPCs) in vivo. We found that hematopoietic tissues were hypoplastic in Ssbp2-/- mice, and the frequency of lymphoid-primed multipotent progenitor cells in bone marrow was reduced. Other significant features of these mice were delayed recovery from 5-fluorouracil treatment and diminished multilineage reconstitution in lethally irradiated bone marrow recipients. Dramatic reduction of Notch1 transcripts and increased expression of transcripts encoding the transcription factor E2a and its downstream target Cdkn1a also distinguished Ssbp2-/- HSPCs from wildtype HSPCs. Finally, a tendency toward coordinated expression of SSBP2 and the AML suppressor NOTCH1 in a subset of the Cancer Genome Atlas AML cases suggested a role for SSBP2 in AML pathogenesis. Collectively, our results uncovered a critical regulatory function for SSBP2 in HSPC gene expression and function.

Original languageEnglish (US)
Pages (from-to)4654-4662
Number of pages9
JournalJournal of Immunology
Volume193
Issue number9
DOIs
StatePublished - Nov 1 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

MD Anderson CCSG core facilities

  • Flow Cytometry and Cellular Imaging Facility
  • Genetically Engineered Mouse Facility
  • Research Animal Support Facility

Fingerprint

Dive into the research topics of 'Requirement for Ssbp2 in hematopoietic stem cell maintenance and stress response'. Together they form a unique fingerprint.

Cite this