title: Requirement for ssbp2 in hematopoietic stem cell maintenance and stress response.
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.
authors.affiliation: Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: June
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kurasawa
authors.affiliation: Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Stem Cell Transplantation, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Karen
authors.initials: K
authors.lastname: Clise-Dwyer
authors.affiliation: Department of Veterinary Medicine and Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Sherry A
authors.initials: SA
authors.lastname: Klumpp
authors.affiliation: Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Radiation Physics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Tailor
authors.affiliation: Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; Graduate Program in Genes and Development, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Raymond
authors.affiliation: Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN 37232; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232; Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232; Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232;
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Brandt
authors.affiliation: Department of Lymphoma and Myeloma, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Richard E
authors.initials: RE
authors.lastname: Davis
authors.affiliation: Division of Pediatrics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Patrick
authors.initials: P
authors.lastname: Zweidler-McKay
authors.affiliation: Department of Hematopathology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; and.
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Amin
authors.affiliation: Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; Graduate Program in Genes and Development, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; Graduate Program in Human Molecular Genetics, Center for Stem Cell and Developmental Biology, and Center for Cancer Genetics and Genomics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030 lnagaraj@mdanderson.org.
authors.forename: Lalitha
authors.initials: L
authors.lastname: Nagarajan
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics; D016130:Immunophenotyping; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D051881:Receptor, Notch1; C504092:Ssbp2 protein, mouse; C075668:Tcf3 protein, mouse