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Learn MoreAfter decades of efforts to simulate juvenile myelomonocytic leukemia (JMML) in mice, with its associated mutations, it is still not clear what causes early demise in JMML patients, although the clinical characteristics have been replicated in older adult mice. By studying a dual-age-specific mouse model, we demonstrate: 1) loss of Pten during the fetal-to-adult hematopoiesis switch (HSC switch) causes sustained fetal hematopoiesis, resulting in juvenile death; 2) myeloid-biased hematopoiesis is associated with the properties of fetal hematopoietic stem cells (HSCs) in mice with Pten deletion; 3) the age specificity of JMML and chronic myelomonocytic leukemia (CMML) depends on the dosage of Pten and Nf1; 4) single-allelic Pten deletion during the HSC switch causes constitutive activation of mitogen-activated protein kinase (MAPK) in mice with Nf1 loss of heterozygosity (LOH); and 5) Nf1 LOH causes monocytosis in juvenile mice with Pten haploinsufficiency but does not cause lethality until adulthood. Our data suggest that one copy of Pten is sufficient to maintain an intact negative feedback loop in the Akt pathway, and, HSC function in reconstitution despite MAPK being constitutively activated in juvenile mice with Pten+/DNf1LOH. However, two copies of Pten are required to maintain the integrity of the MAPK pathway in juvenile mice with Nf1 haploinsufficiency. We provide a proof-of-concept that disassociated age-specific hematopoiesis contributes to leukemogenesis and pediatric demise. Our data indicate that previous investigations of Pten function in wild type mice may not have reflected the impact of Pten loss in mice with Nf1 mutation or other genetic defects. SOURCE: Lucy Liu (ylliu19@stanford.edu) - University of Arkansas for Medical Sciences
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