AML1 deletion in adult mice causes splenomegaly and lymphomas

Abstract

AML1 (RUNX1) encodes a DNA-binding subunit of the CBF transcription factor family and is required for the establishment of definitive hematopoiesis. AML1 is one of the most frequently mutated genes associated with human acute leukemia, suggesting that genetic alterations of the gene contribute to leukemogenesis. Here, we report the analysis of mice carrying conditional AML1 knockout alleles that were inactivated using the Cre/loxP system. AML1 was deleted in adult mice by inducing Cre activity to replicate AML1 deletions found in human MDS, familial platelet disorder and rare de novo human AML. At a latency of 2 months after induction, the thymus was reduced in size and frequently populated by immature double negative thymocytes, indicating defective Tlymphocyte maturation, resulting in lymphatic diseases with 50% penetrance, including atypical hyperplasia and thymic lymphoma. Metastatic lymphomas to the liver and the meninges were observed. Mice also developed splenomegaly with an expansion of the myeloid compartment. Increased Howell-Jolly body counts indicated splenic hypofunction. Thrombocytopenia occurred due to immaturity of mini-megakaryocytes in the bone marrow. Together with mild lymphocytopenia in the peripheral blood and increased fractions of immature cells in the bone marrow, AML1 deficient mice display features of a myelodysplastic syndrome, suggesting a preleukemic state.

PEBP2-β/CBF-β–dependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis

“…Their central role in orchestrating proper differentiation of hematopoietic stem cells is underscored by the ablation of definitive hematopoiesis in Runx1 or Pebp2b Ϫ/Ϫ knockout mice [4][5][6] and an expanded HSC compartment in conditional Runx1-deficient mice. [7][8][9][10] However, although the overall biologic functions of RUNX1 are becoming clear, how these functions are controlled at the molecular level and the contribution of PEBP2-␤ remain to be fully determined.The evolutionarily conserved partner protein PEBP2-␤ is known to enhance DNA binding ability of all 3 mammalian RUNX proteins (RUNX1-3) by inducing allosteric change of DNA binding Runt domain without direct DNA contact. In addition, we have previously reported that PEBP2-␤ regulates RUNX1 metabolic stability by preventing its ubiquitin-mediated degradation.…”

Allogeneic bone marrow transplantation and donor lymphocyte infusion in a mouse model of irradiation-induced myelodysplastic/myeloproliferation syndrome (MD/MPS): evidence for a graft-versus-MD/MPS effect

“…33 In recently published mouse studies, it was shown that deletion of AML1, transgenic expression of EVI1 or NUP98-HOXD13, as well targeting of Dido lead to the development of a hematopathological picture similar to human MDS or MD/MPS. [20][21][22][23] These recent studies have provided key information on the molecular basis of MDSFin particular, how selected genetic abnormalities may lead to defects in proliferation and differentiation and to leukemic transformation in MDS and MD/MPS. [20][21][22][23] Our model of radiation-induced MDS may be particularly suited for the study of the therapeutic value of alloHSCT and DLI.…”

“…A limited number of genetically engineered mouse models of MDS exists, and these were developed with the objective of unraveling the molecular etiology and pathogenesis of MDS. [20][21][22][23] Here, we describe a radiation-induced model of MD/MPS in mice, which, in addition, is suitable for the study of allograft-mediated immune effects. Using this model, we were able to experimentally demonstrate that MD/MPS is susceptible to DLI in the context of MHC-mismatched alloBMT.…”

“…35 Rather than giving rise to an accelerated onset and/or elevated incidence of such a primary malignant myeloid disease, high-dose TBI in our model led to the observed dysplastic/proliferative disorder in which leukemic transformation merely seemed to occur as a complication. Future work will indicate whether the chromosomal defects of the SJL/J radiationinduced AML, or one of the molecular defects described in known genetically engineered mouse MDS or MD/MPS models, [20][21][22][23] are involved in the current model.…”

“…[16][17][18][19] Other than these case reports and small series, clinical data on graft-versus-MDS responses are limited. In addition, animal models of MDS are scarce: although genetically engineered mouse MDS models have been reported on, [20][21][22][23] their importance mainly lies in the study of the molecular basis and pathogenesis of MDS. In particular, GvM effects in MDS have so far not been studied experimentally.…”