Developmentally induced Mll1 loss reveals defects in postnatal haematopoiesis

Abstract

The Mixed Lineage Leukemia (MLL) gene is disrupted by chromosomal translocations in acute leukemia, producing a fusion oncogene with altered properties relative to the wild-type gene. Murine loss-of-function studies have demonstrated an essential role for Mll in developing the haematopoietic system, yet studies using different conditional knockout models have yielded conflicting results regarding the requirement for Mll during adult steady-state haematopoiesis. Here, we employ a loxP-flanked Mll allele (MllF) and a developmentally-regulated, haematopoietic-specific VavCre transgene to re-assess the consequences of Mll loss in the haematopoietic lineage, without the need for inducers of Cre recombinase. We show that VavCre;Mll mutants exhibit phenotypically normal fetal haematopoiesis, but rarely survive past 3 weeks of age. Surviving animals are anemic, thrombocytopenic and exhibit a significant reduction in bone marrow haematopoietic stem/progenitor populations, consistent with our previous findings using the inducible Mx1Cre transgene. Furthermore, the analysis of VavCre mutants revealed additional defects in B-lymphopoiesis that could not be assessed using Mx1Cre-mediated Mll deletion. Collectively, these data support the conclusion that Mll plays an essential role in sustaining postnatal haematopoiesis.

Epigenetics of hematopoiesis and hematological malignancies

“…Its deletion in mice causes embryonic lethality at E16.5, with fetal livers having dramatically reduced numbers of HSCs, indicating an essential role for Mll in embryonic hematopoiesis (Hess et al 1997;Ernst et al 2004;McMahon et al 2007). Mll is also essential for sustaining postnatal hematopoiesis, as a conditional deletion in postnatal mice with hematopoietic-specific Vav-Cre leads to a multilineage defect in differentiation and a decrease in adult hematopoietic progenitors, with a fatal bone marrow failure occurring at ∼3 wk of age (Jude et al 2007;Gan et al 2010).…”

The histone methyltransferase activity of mll1 is dispensable for hematopoiesis and leukemogenesis

“…Mature lymphoid and myeloid populations in the bone marrow and blood of ΔSET animals were present at normal frequencies (P.E., data not shown). Because HSPCs are extremely sensitive to loss of Mll1 (Gan et al, 2010;Jude et al, 2007;McMahon et al, 2007), we carefully assessed the phenotype and function of HSPCs in ΔSET mutant mice.…”

Connectivity mapping identifies HDAC inhibitors for the treatment of t(4;11)-positive infant acute lymphoblastic leukemia

“…The most common MLL translocation among infant ALL patients, occurring in about 50% of the cases, is t(4;11) generating the fusion product MLL-AF4 (refs.1,5) as well as, in most instances, the reciprocal fusion product AF4-MLL. 6 Given the importance of the MLL gene in regulating transcription during definitive hematopoiesis, 7,8 interruptions of MLL lead to abnormal gene expression patterns that presumably favor leukemia development. 9,10 These unique gene expression profiles are to some extent mediated by leukemia-specific histone modifications, such as histone 3 lysine 79 dimethylation (H3K79me2), established via recruitment of DOT1L by MLL fusion partners.…”