ABSTRACT
RUNX1/AML1 is among the most commonly mutated genes in human leukemia. Haploinsufficiency of RUNX1 causes familial platelet disorder with predisposition to myeloid malignancies (FPD/MM). However, the molecular mechanism of FPD/MM remains unknown. Here we show that murine Runx1(+/-) hematopoietic cells are hypersensitive to granulocyte colony-stimulating factor (G-CSF), leading to enhanced expansion and mobilization of stem/progenitor cells and myeloid differentiation block. Upon G-CSF stimulation, Runx1(+/-) cells exhibited a more pronounced phosphorylation of STAT3 as compared with Runx1(+/+) cells, which may be due to reduced expression of Pias3, a key negative regulator of STAT3 signaling, and reduced physical sequestration of STAT3 by RUNX1. Most importantly, blood cells from a FPD patient with RUNX1 mutation exhibited similar G-CSF hypersensitivity. Taken together, Runx1 haploinsufficiency appears to predispose FPD patients to MM by expanding the pool of stem/progenitor cells and blocking myeloid differentiation in response to G-CSF.
Subject(s)
Core Binding Factor Alpha 2 Subunit/genetics , Drug Resistance/genetics , Genetic Predisposition to Disease , Granulocyte Colony-Stimulating Factor/pharmacology , Haploinsufficiency , Leukemia, Myeloid, Acute/genetics , Animals , Blood Platelet Disorders/genetics , Bone Marrow Cells/drug effects , Bone Marrow Cells/metabolism , Cytokines/pharmacology , Disease Models, Animal , Gene Expression Regulation, Leukemic/drug effects , Genotype , Granulocyte Colony-Stimulating Factor/administration & dosage , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/metabolism , Humans , Leukemia, Myeloid, Acute/pathology , Mice , Molecular Chaperones/genetics , Molecular Chaperones/metabolism , Mutation , Phosphorylation , Protein Binding , Protein Inhibitors of Activated STAT/genetics , Protein Inhibitors of Activated STAT/metabolism , Receptors, CXCR4/genetics , Receptors, CXCR4/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effectsABSTRACT
RUNX1 and CBFB are among the most frequently mutated genes in human leukemias. Genetic alterations such as chromosomal translocations, copy number variations and point mutations have been widely reported to result in the malfunction of RUNX transcription factors. Leukemias arising from such alterations in RUNX family genes are collectively termed core binding factor (CBF) leukemias. Although adult CBF leukemias generally are considered a favorable risk group as compared with other forms of acute myeloid leukemia, the 5-year survival rate remains low. An improved understanding of the molecular mechanism for CBF leukemia is imperative to uncover novel treatment options. Over the years, retroviral transduction-transplantation assays and transgenic, knockin and knockout mouse models alone or in combination with mutagenesis have been used to study the roles of RUNX alterations in leukemogenesis. Although successful in inducing leukemia, the existing assays and models possess many inherent limitations. A CBF leukemia model which induces leukemia with complete penetrance and short latency would be ideal as a platform for drug discovery. Here, we summarize the currently available mouse models which have been utilized to study CBF leukemias, discuss the advantages and limitations of individual experimental systems, and propose suggestions for improvements of mouse models.
