Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors.
The Mixed Lineage Leukemia (MLL) gene is essential for embryonic hematopoietic stem cell (HSC) development, but its role during adult hematopoiesis is unknown. Using an inducible knockout model, we demonstrate that Mll is essential for the maintenance of adult HSCs and progenitors, with fatal bone marrow failure occurring within 3 weeks of Mll deletion. Mll-deficient cells are selectively lost from mixed bone marrow chimeras, demonstrating their failure to self-renew even in an intact bone marrow environment. Surprisingly, HSCs lacking Mll exhibit ectopic cell-cycle entry, resulting in the depletion of quiescent HSCs. In contrast, Mll deletion in myelo-erythroid progenitors results in reduced proliferation and reduced response to cytokine-induced cell-cycle entry. Committed lymphoid and myeloid cells no longer require Mll, defining the early multipotent stages of hematopoiesis as Mll dependent. These studies demonstrate that Mll plays selective and independent roles within the hematopoietic system, maintaining quiescence in HSCs and promoting proliferation in progenitors.
Jude
Craig D
CD
Department of Genetics and Norris Cotton Cancer Center, Dartmouth Medical School, 725 Remsen, HB7400, Hanover, NH 03755, USA.
Climer
Leslie
L
Xu
Diyong
D
Artinger
Erika
E
Fisher
Jill K
JK
Ernst
Patricia
P
D000483:Alleles; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002452:Cell Count; D016923:Cell Death; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D049109:Cell Proliferation; D002470:Cell Survival; D002678:Chimera; D015672:Erythroid Precursor Cells / Q000166:cytology; D005091:Exons / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology; D023461:Myeloid Progenitor Cells / Q000166:cytology; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid
D051788:Myeloid-Lymphoid Leukemia Protein