Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells.
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.
Opferman
Joseph T
JT
Howard Hughes Medical Institute, Department of Cancer Immunology and AIDS, Pathology and Medicine, Harvard Medical School, Boston, MA 02115, USA.
Iwasaki
Hiromi
H
Ong
Christy C
CC
Suh
Heikyung
H
Mizuno
Shin-ichi
S
Akashi
Koichi
K
Korsmeyer
Stanley J
SJ
D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D002452:Cell Count; D019070:Cell Lineage; D048430:Cell Shape; D002470:Cell Survival; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D017353:Gene Deletion; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006706:Homeostasis; D015850:Interleukin-6 / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000502:physiology; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D011070:Poly I-C / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000494:pharmacology; D014161:Transduction, Genetic
D015850:Interleukin-6; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D019089:Stem Cell Factor; D011070:Poly I-C