| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Liang, Hong Estrov, Zeev Davis, Richard E. Zweidler-McKay, Patrick Clise-Dwyer, Karen Klumpp, Sherry A. Kurasawa, Yasuhiro Amin, Hesham M. Raymond, Aaron C. Brandt, Stephen J. Li, June Wang, Yang Nagarajan, Lalitha Tailor, Ramesh C. |
| Description |
Author Affiliation: Li J ( Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030); Kurasawa Y ( Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030); Wang Y ( Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030); Clise-Dwyer K ( Department of Stem Cell Transplantation, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030); Klumpp SA ( Department of Veterinary Medicine and Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030); Liang H ( Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030); Tailor RC ( Department of Radiation Physics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030); Raymond AC ( Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030); Estrov Z ( Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030); Brandt SJ ( Department of Medicine, Vanderbilt University, Nashville, TN 37232); Davis RE ( Department of Lymphoma and Myeloma, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030); Zweidler-McKay P ( Division of Pediatrics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030); Amin HM ( Department of Hematopathology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030); Nagarajan L ( Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030) |
| 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 wild-type 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. |
| ISSN |
00221767 |
| e-ISSN |
15506606 |
| DOI |
10.4049/jimmunol.1300337 |
| Journal |
The Journal of Immunology |
| Issue Number |
9 |
| Volume Number |
193 |
| Language |
English |
| Publisher |
The American Association of Immunologists |
| Publisher Date |
2014-11-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Cell Differentiation Dna-binding Proteins Metabolism Hematopoietic Stem Cells Cytology Stress, Physiological Animals Basic Helix-loop-helix Transcription Factors Genetics Bone Marrow Pathology Bone Marrow Transplantation Gene Expression Hematopoiesis Homeostasis Immunophenotyping Mice Mice, Knockout Phenotype Receptor, Notch1 Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Discipline Immunology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Immunology and Allergy Immunology |
