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Developmentally Induced Mll1 Loss Reveals Defects in Postnatal Haematopoiesis

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Developmentally Induced Mll1 Loss Reveals Defects in Postnatal Haematopoiesis Leukemia (2010) 24, 1732–1741 & 2010 Macmillan Publishers Limited All rights reserved 0887-6924/10 www.nature.com/leu ORIGINAL ARTICLE Developmentally induced Mll1 loss reveals defects in postnatal haematopoiesis T Gan1,3, CD Jude1,3, K Zaffuto1 and P Ernst1,2 1Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH, USA and 2Department of Microbiology and Immunology, Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH, USA The mixed lineage leukemia (MLL) gene is disrupted by motifs5–7 and chromatin recognition motifs.8,9 Much of the chromosomal translocations in acute leukemia, producing a chromatin-targeting activity is retained in the N-terminus and is fusion oncogene with altered properties relative to the wild-type thus shared between MLL and oncogenic MLL fusion proteins. gene. Murine loss-of-function studies have shown an essential role for Mll in developing the haematopoietic system, yet Therefore, it is not surprising that many genes identified as studies using different conditional knockout models have overexpressed in cells harboring MLL translocations are also yielded conflicting results regarding the requirement for Mll natural MLL target genes.10 The extent to which MLL fusion during adult steady-state haematopoiesis. In this study, we proteins simply hyperactivate a natural MLL-dependent haema- F used a loxP-flanked Mll allele (Mll ) and a developmentally topoietic program or alternatively, exhibit neomorphic activity regulated, haematopoietic-specific VavCre transgene to reas- (acquiring and deregulating new target genes), remains unclear, sess the consequences of Mll loss in the haematopoietic lineage, without the need for inducers of Cre recombinase. but this distinction is critical for the development of targeted We show that VavCre;Mll mutants exhibit phenotypically therapeutics. normal fetal haematopoiesis, but rarely survive past 3 weeks To understand the normal role of wild-type Mll gene in the of age. Surviving animals are anemic, thrombocytopenic and haematopoietic system, our group and others have performed exhibit a significant reduction in bone marrow haematopoietic gene disruption experiments to generate loss-of-function stem/progenitor populations, consistent with our previous alleles using a variety of strategies.11–15 Owing to the large findings using the inducible Mx1Cre transgene. Furthermore, the analysis of VavCre mutants revealed additional defects in and complex nature of the Mll1 locus, none of these gene B-lymphopoiesis that could not be assessed using Mx1Cre- disruptions produce null alleles, and all (with the exception of mediated Mll deletion. Collectively, these data support the the SET (Su(var)3-9, enhancer of zeste, trithorax) domain conclusion that Mll has an essential role in sustaining postnatal deletion14) result in embryonic lethality when homozygous. haematopoiesis. The age of embryonic lethality varies amongst alleles, suggesting Leukemia (2010) 24, 1732–1741; doi:10.1038/leu.2010.171; that residual function of the different alleles may cause the published online 19 August 2010 Keywords: haematopoiesis; MLL; Vav; interferon; stem cells variable results reported. Furthermore, Mll expression in the embryo is dynamic and widespread and the cause of lethality has not been clearly elucidated. For these reasons, we and others,15 have developed conditional knockout alleles to more precisely assess the role of Mll in adult haematopoietic cell types and in other tissues. Introduction To produce a conditional loss-of-function allele, our group generated an Mll allele in which exons 3 and 4 are loxP-flanked The treatment of childhood leukemia has improved dramatically (Mll F).16 We demonstrated that the excision of exons 3 in the last five decades. However, patients with certain and 4 (producing the MllDN allele) results in an in-frame deletion cytogenetic abnormalities do not effectively respond to the and the resulting MLLDN protein can not be imported into conventional chemotherapy, particularly those defined by the nucleus because of the loss of nuclear localization motifs. translocations in the mixed lineage leukemia (MLL) locus at The cytoplasmic localization was demonstrated in cells expres- 11q23. It remains unclear why this group has a particularly poor sing an epitope-tagged version of the MLLDN protein as well as 1 outcome independent from patient age. Significant advances in Mll-deleted primary cells.16 In addition, the AT hooks,5 have been made in understanding the molecular consequences methylation status-specific DNA recognition motifs,6,7 and of 11q23 translocations using mouse models, but the need for subnuclear targeting motifs17 are lacking in the MLLDN protein. new strategies to target this cytogenetically defined group of These motifs are essential for transformation in the context leukemias justifies further investigation into molecular pathways of MLL–ENL (eleven;nineteen leukemia) fusion oncoproteins.6 2 regulated by MLL. In an independent study, McMahon et al.15 generated an Mll F The protein encoded by the MLL gene (Mll1 in mouse) is a allele, in which exons 8 and 9 are excised, also resulting in an large nuclear chromatin-modifying protein that encodes histone in-frame deletion. The protein produced from this allele is likely 3,4 methyltransferase activity. In addition to its methyltransferase unstable; MLL is undetectable by immunoblot in mutant fetal activity, MLL possesses sequence-nonspecific DNA recognition liver extracts. Interestingly, both gene disruption strategies result in several very similar phenotypes such as embryonic lethality of Correspondence: Dr P Ernst, Department of Genetics, Norris Cotton germline homozygotes beginning at BE12.5, inefficient fetal Cancer Center, Dartmouth Medical School, 725 Remsen, HB7400, liver haematopoiesis and adult bone marrow cells that fail to Hanover, NH, 03755, USA. engraft secondary recipients. However, one significant pheno- E-mail: [email protected] 3 typic difference distinguished these two conditional knockout These authors contributed equally to this work. 15 Received 14 January 2010; revised 13 June 2010; accepted 6 July models. In the McMahon et al. study, the pan-haematopoietic, 2010; published online 19 August 2010 VavCre-mediated deletion resulted in efficient Mll excision Mll1 is essential for postnatal haematopoiesis T Gan et al 1733 in all haematopoietic cells, with no effect on steady-state mice were obtained from Jackson Labs (stock no. 006148). haematopoietic populations. Despite normal steady-state Embryo age was defined as day 0.5 at 0800 hours the day of haematopoiesis, bone marrow cells from these animals exhi- plug observation. To screen out germline and mosaic expression bited a severe defect in engrafting secondary recipients. of the VavCre transgene, embryos harboring the RosaYFP allele Thus, based on this mouse model, the authors concluded that were imaged after dissection or non-haematopoietic tissues Mll is only required for the process of regenerating the were assessed for Mll excision using a quantitative genomic PCR haematopoietic system but not for steady-state haemato- assay16 using tail, limb bud, somite or head genomic DNA. poiesis. In contrast, our studies using the inducible Mx1Cre A similar approach was used to screen adult VavCre animals, transgene18 demonstrated an absolute requirement for Mll in using ear, tail or liver genomic DNA. steady-state as well as regenerative haematopoiesis. We observed a significant reduction in haematopoietic stem cell function as early as 4 days after deletion of Mll followed Flow cytometry and differential blood counts by a rapid decline in most bone marrow cells and lethality 2–3 Bone marrow cells were prepared and lineage staining was 16, 0 weeks after deletion.16 performed as previously described except that the F ab2 anti- Two major differences between these mouse models may rat conjugate was a PE-Cy5.5 reagent (Invitrogen, Carlsbad, CA, account for the different conclusions. First, the proteins encoded USA). Splenocytes and thymocytes were prepared by trituration by the two different alleles may retain some quantitatively through a 40-micron nylon filter. For splenocytes and bone or qualitatively different residual functions. Second, the method marrow, RBC lysis buffer (eBioscience, San Diego, CA, USA) of excision (Mx1Cre versus VavCre) may impact on the effects was used to remove red blood cells. For adult bone marrow, of Mll loss. The Mx1Cre transgene is widely used to evade lineage cocktail consisted of unlabeled rat anti-Gr-1, Mac-1, embryonic lethality and introduce Cre-mediated gene mani- interleukin-7Ra, Ter119, CD3, CD4, CD8, B220 and CD19, all pulations into the haematopoietic system.19 The induction of from Invitrogen except that interleukin-7Ra antibody was Cre expression is initiated in adult animals by the injection obtained from eBioscience. For the fetal liver analyses, lineage of polyinosinic–polycytidylic acid (pI:pC), a double stranded NA cocktail lacked the Mac-1 antibody. In some experiments, goat analog. Toll-like receptor 3 mediated recognition of double anti-rat APC (BD Biosciences, San Jose, CA, USA) was used stranded RNA initiates the expression of type I interferons (IFNs), in conjunction with Sca-1 biotin, c-Kit PE, CD48 FITC and which result in the activation of the Mx1Cre transgene.18 streptavidin-PECy5.5 all from BD Biosciences. T cell analyses Systemic IFNs affect many developing and mature haemato- utilized anti-CD3, CD4, CD8, CD25, CD44, CD45.1 and poietic
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