Intercepting progression to leukemia in a novel runx1-fpd mouse model

Germline RUNX1 haploinsufficiency predisposes to myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) in RUNX1 familial platelet disorder (RUNX1-FPD). To study the molecular pathogenesis underlying transition to leukemia in RUNX1-FPD, we have developed novel compound mutant mice as an in vivo model: we combined germline Runx1 haploinsufficiency with a defect in DNA mismatch repair, in an attempt to mimic disease progression in patients through additional mutation acquisition and formation of a mutationally diverse stem cell pool. Strikingly, compound mutant mice developed MDS/AML with a 30 % penetrance, and with hallmark expansion of myeloid-biased hematopoietic stem and progenitor cells (HSPCs). Upon congenic transplantation, sorted immunophenotypic stem cells from leukemic mice and total bone marrow from preleukemic mice caused AML in recipient mice indicating a stem cell origin of leukemia in our new model. Comprehensive transcriptomic analyses of HSPCs identified dysregulation of inflammation-mediated signaling via transcription factors (including TNF-α signaling via NF-κB and JAK-STAT3 signaling), with affected pathways being highly similar to molecular findings in RUNX1-FPD patients. Restoration of Runx1 using a retroviral vector system led to myeloid differentiation and impaired self-renewal of AML cells, suggesting that sustained Runx1 downregulation remains critical for leukemic stem cells in this setting. In ongoing studies, we are examining whether leukemic progression can be prevented or delayed by targeting inflammation-mediated signaling and transcription factor networks – akin to a concept of cancer interception. In addition to new insights into causative molecular pathways, our novel longitudinal RUNX1-FPD-to-AML progression model provides an innovative preclinical system for the testing of preemptive intervention strategies in RUNX1-FPD. Germline RUNX1 haploinsufficiency predisposes to myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) in RUNX1 familial platelet disorder (RUNX1-FPD). To study the molecular pathogenesis underlying transition to leukemia in RUNX1-FPD, we have developed novel compound mutant mice as an in vivo model: we combined germline Runx1 haploinsufficiency with a defect in DNA mismatch repair, in an attempt to mimic disease progression in patients through additional mutation acquisition and formation of a mutationally diverse stem cell pool. Strikingly, compound mutant mice developed MDS/AML with a 30 % penetrance, and with hallmark expansion of myeloid-biased hematopoietic stem and progenitor cells (HSPCs). Upon congenic transplantation, sorted immunophenotypic stem cells from leukemic mice and total bone marrow from preleukemic mice caused AML in recipient mice indicating a stem cell origin of leukemia in our new model. Comprehensive transcriptomic analyses of HSPCs identified dysregulation of inflammation-mediated signaling via transcription factors (including TNF-α signaling via NF-κB and JAK-STAT3 signaling), with affected pathways being highly similar to molecular findings in RUNX1-FPD patients. Restoration of Runx1 using a retroviral vector system led to myeloid differentiation and impaired self-renewal of AML cells, suggesting that sustained Runx1 downregulation remains critical for leukemic stem cells in this setting. In ongoing studies, we are examining whether leukemic progression can be prevented or delayed by targeting inflammation-mediated signaling and transcription factor networks – akin to a concept of cancer interception. In addition to new insights into causative molecular pathways, our novel longitudinal RUNX1-FPD-to-AML progression model provides an innovative preclinical system for the testing of preemptive intervention strategies in RUNX1-FPD.