Program: Oral and Poster Abstracts
Session: 636. Myelodysplastic Syndromes – Basic and Translational Studies: Poster II
In order to understand the mechanisms underlying the development of MDS/AML in GATA2 deficiency we developed and analyzed a unique mouse model. The previously characterized Gata2+9.5+/- mouse has an intronic regulatory region mutation identical to one found in some patients. However, these mice do not develop MDS/AML spontaneously. We hypothesized that crossing these mice to other MDS/AML prone strains would accelerate the progression of MDS/AML. Specific HOX genes are implicated in this disease process. GATA2-deficient patients often develop monosomy 7 and ASXL1 mutations, both of which lead to the overexpression of HOX genes including HOXA9. The known AML translocation t(2;11)(q31;p15) results in the fusion of NUP98 and HOXD13 (NHD13) and the upregulation of HOX gene expression. Gata2 was identified in a mouse retroviral insertion screen as a potential collaborator in NHD13-mediated leukemogenesis. We hypothesized that hematopoietic specific Hox gene overexpression in a mouse with germline Gata2 haploinsufficiency would lead to the development of MDS/AML. This was done using the established NHD13 transgenic strain crossed to the Gata2+9.5+/- strain. The NHD13 mice express the fusion protein under the control of the hematopoietic specific vav promoter, and have up-regulation of Hoxa5, Hoxa7, Hoxa9, and Hoxa10. Secondly, elevated Flt3 ligand levels have been detected in GATA2-deficient patients as they progress from normal bone marrow morphology to MDS/AML. To model the hyper-activation of the receptor Flt3 by Flt3 ligand, we used a model of constitutively active Flt3, the Flt3-ITD mouse.
Gata2+9.5+/- mice were bred to the NHD13 and the Flt3-ITD transgenic strains and compound heterozygotes were analyzed. Gata2+9.5+/-;NHD13 compound heterozygous mice were born normally and at Mendelian ratios. No significant differences in blood cell counts were noted in Gata2+9.5+/-;NHD13 compound heterozygotes until disease progression. These mice developed aggressive AML at 9-14 months of age, similar ages and rates as the NHD13 only mice. Whereas compound Gata2+9.5+/-;Flt3-ITD mice are also born in Mendelian ratios, starting at 10 weeks of age they developed B-cell lymphopenia, similar to that which is seen in human GATA2 deficiency patients displaying B-cell loss early in disease. The Gata2+9.5+/-;Flt3-ITD mice exhibited increased circulating c-Kit-positive cells in the peripheral blood. Studies to further characterize hematopoiesis in the Gata2+9.5+/-;Flt3-ITD mice, and analyze for the development of MDS/AML are in progress. The Gata2+9.5+/-;Flt3-ITD mouse model holds promise for the further study of MDS/AML in the context of GATA2 haploinsufficiency.
Disclosures: Aplan: NIH Office of Technology Transfer: Patents & Royalties .
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