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 single-stranded DNA-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. Here, 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 towards 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.

Clinical and biological significance ofde novoCD5+ diffuse large B-cell lymphoma in Western countries

“…SSBP2 has a critical regulatory role in the transcriptional program of hematopoietic stem and progenitor cells in vivo , via modulating the abundance and function of multiple transcription cofactors including LIM domain-binding protein 1 (LDB1), LMO, and LHX. In mouse models, loss of SSBP2 resulted in hypoplastic hematopoietic tissues and impaired hematopoiesis and was associated with shortened lifespan and greater susceptibility to B-cell lymphomas [34, 35, 48]. Prognostic significance of CD5 expression in SSBP2 + and SSBP2 − DLBCL patients also suggests a tumor-suppressor function of SSBP2 for CD5 signaling.…”

The loss of nuclear expression of single-stranded DNA binding protein 2 of gastric adenocarcinoma and its prognostic role: Analysis of molecular subtype

“…One of the known functions of SSBP2 is to bind LDB1 and regulate LDB1 activity. LDB1 regulates the differentiation of luminal cells in the gastrointestinal tract [ 17 ] and cardiomyocytes [ 18 ] and is also involved in cancer progression [ 11 , 19 ]. Several studies on the promoter methylation of SSBP2 in tumors have shown that it is one of the genes downregulated by methylation [ 13 – 15 , 20 , 21 ].…”

“…Single-stranded DNA binding protein 2 (SSBP2) is known to be a candidate tumor suppressor in patients with myeloid leukemia located at chromosome 5q14 [ 8 – 10 ]. SSBP2 binds to the transcriptional cofactor Lim-domain-binding protein 1 (LDB1) and enhances LDB1 stability to regulate gene expression [ 11 ]. The role of SSBP2 has also been studied in several solid tumors including hepatocellular carcinoma, gallbladder cancer, esophageal squamous cell carcinoma, and prostate cancer.…”

LIM-Only Protein 4 (LMO4) and LIM Domain Binding Protein 1 (LDB1) Promote Growth and Metastasis of Human Head and Neck Cancer (LMO4 and LDB1 in Head and Neck Cancer)

“…LMO2 [51], LDB1 [52], and SSBP2 [53] are required for the function or maintenance of hematopoietic stem cells, and Ldb1 has also been shown to be essential to the survival of intestinal epithelial stem cells [54]. As the malignant counterparts of these cells have been found in a number of epithelial neoplasms, including HNSCC (reviewed in [55]) and have been implicated in metastasis [56, 57], tumor angiogenesis [58], and lymphangiogenesis [59] (see below), we speculate that LIM-only, LIM domain-binding, and single-stranded DNA-binding proteins regulate both normal and cancer stem cells.…”