Understanding and Targeting Progression in a Novel Mouse Model of RUNX1 Familial Platelet Disorder [mouse scRNA]
Germline heterozygous mutations in RUNX1 are foundational for the development of familial platelet disorder (RUNX1-FPD) with predisposition to hematologic malignancies. The development of malignant disease involves the acquisition of additional somatic mutations, followed by clonal expansion. To simulate this process which often takes decades to unfold in humans, we developed a mouse model which combined Runx1 haploinsufficiency with defective DNA mismatch repair (MMR, Msh2 KO) to speed the accumulation of somatic mutations acquired with aging. The resultant double mutant mice presented with expansion of myeloid-biased hematopoietic stem and progenitor cells (HSPCs) and subsequent transformation to an aggressive and transplantable acute myeloid leukemia (AML), thus modeling RUNX1-FPD progression. Adoptive transfer experiments identified phenotypic myeloid-biased multipotent progenitors (MPPMy; Lin-cKit+Sca-1+Flt3-CD150+CD48+/-) as the leukemia-initiating cells in this model. Transcriptomic analyses identified dysregulation of myeloid transcription factors and inflammatory signaling – a finding which was recapitulated in sorted HSPCs from patients with RUNX1-FPD. Of note, even cells from preleukemic Runx1+/-Msh2-/- mice gave rise to AML in congenic transplant recipients. Strikingly, preemptive treatment with JAK1/2 and STAT3 inhibitors at the preleukemic stage led to a significant delay in progression and prolonged overall survival. Overall, our studies identify a novel mouse model of RUNX1-FPD to AML transition and provide a means to investigate preventative intervention strategies in RUNX1-FPD. Overall design: RNA-seq profiling of Runx1+/-Msh2-/- Lin-cKit+ cells at a preleukemic (3 months) and a leukemic (6 months old) time point.