Blood Journal
Leading the way in experimental and clinical research in hematology

Depletion of Sf3b1 impairs proliferative capacity of hematopoietic stem cells but is not sufficient to induce myelodysplasia

  1. Changshan Wang1,2,
  2. Goro Sashida1,2,
  3. Atsunori Saraya1,2,
  4. Reiko Ishiga3,
  5. Shuhei Koide1,2,
  6. Motohiko Oshima1,2,
  7. Kyoichi Isono4,
  8. Haruhiko Koseki4, and
  9. Atsushi Iwama1,2
  1. 1Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan;
  2. 2Japan Science and Technology Corporation, Core Research for Evolutional Science and Technology, Gobancho, Chiyoda-ku, Tokyo, Japan;
  3. 3Chromosome Unit, Central Laboratory, Tokyo Medical University, Tokyo, Japan; and
  4. 4Laboratory for Developmental, RIKEN Research Center for Integrative Medical Sciences, RCAI-IMS, Yokohama, Japan

Key Points

  • The level of Sf3b1 expression is critical for the proliferative capacity of hematopoietic stem cells.

  • Haploinsufficiency for Sf3b1 is not sufficient to induce a RARS-like phenotype in mice.

Abstract

Numerous studies have recently reported mutations involving multiple components of the messenger RNA (mRNA) splicing machinery in patients with myelodysplastic syndrome (MDS). SF3B1 is mutated in 70% to 85% of refractory anemia with ringed sideroblasts (RARS) patients and is highly associated with the presence of RARS, although the pathological role of SF3B1 mutations in MDS-RARS has not been elucidated yet. Here, we analyzed the function of pre-mRNA splicing factor Sf3b1 in hematopoiesis. Sf3b1+/− mice maintained almost normal hematopoiesis and did not develop hematological malignancies during a long observation period. However, Sf3b1+/− cells had a significantly impaired capacity to reconstitute hematopoiesis in a competitive setting and exhibited some enhancement of apoptosis, but they did not show any obvious defects in differentiation. Additional depletion of Sf3b1 with shRNA in Sf3b1+/− hematopoietic stem cells (HSCs) severely compromised their proliferative capacity both in vitro and in vivo. Finally, we unexpectedly found no changes in the frequencies of sideroblasts in either Sf3b1+/− erythroblasts or cultured Sf3b1+/− erythroblasts expressing shRNA against Sf3b1. Our findings indicate that the level of Sf3b1 expression is critical for the proliferative capacity of HSCs, but the haploinsufficiency for Sf3b1 is not sufficient to induce a RARS-like phenotype.

  • Submitted December 17, 2013.
  • Accepted April 9, 2014.
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