Obligate Role of Anti-Apoptotic MCL-1 in the Survival of Hematopoietic Stem Cells

TLDR

Apoptosis regulates hematopoietic stem cell numbers, but the specific BCL‑2 family members involved in HSC homeostasis remain unclear. The study aimed to test whether MCL‑1, highly expressed in HSCs and regulated by growth factors, regulates HSC homeostasis. Using inducible Mcl‑1 deletion in mice, the authors showed that growth factors upregulate Mcl‑1 transcription and that MCL‑1 is required for survival of purified bone marrow progenitors. Inducible deletion of Mcl‑1 ablated bone marrow, eliminated early progenitor populations including HSCs, and demonstrated that MCL‑1 is a critical, tissue‑specific regulator of early hematopoietic progenitor homeostasis.

Abstract

Apoptosis is important in controlling hematopoietic stem cell (HSC) numbers. However, the specific BCL-2 family member(s) that regulate HSC homeostasis are not precisely defined. We tested myeloid leukemia-1 (MCL-1) as an attractive candidate that is highly expressed in HSCs and regulated by growth factor signals. Inducible deletion of Mcl-1 in mice resulted in ablation of bone marrow. This resulted in the loss of early bone marrow progenitor populations, including HSCs. Moreover, growth factors including stem cell factor increased transcription of the Mcl-1 gene and required MCL-1 to augment survival of purified bone marrow progenitors. Deletion of Mcl-1 in other tissues, including liver, did not impair survival. Thus, MCL-1 is a critical and specific regulator essential for ensuring the homeostasis of early hematopoietic progenitors.