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MicroRNA-7 modulates Rb1 and c-Myc expression in myeloid leukemias harboring c-Kit mutations

ABSTRACT: The receptor tyrosine kinase, c-kit, plays a pivotal role in hematopoiesis and self-renewal. Aberrant activation of c-kit can be induced by genetic alterations and is thought to confer therapeutic resistance in leukemia. Significantly, the c-kit D816V mutation is a well-known indicator of poor prognosis in acute myeloid leukemias harboring t(8;21) chromosomal translocations; however, the mechanism by which this mutation promotes therapeutic resistance is still unclear. Our study identified that miR-7 directly targets Retinoblastoma-like Protein 1 (Rb1) and is regulated by the MEK pathway. In addition, we also found that c-Myc is upregulated by the D816V mutation, and is indirectly downregulated by miR-7.

ORGANISM(S): Rattus norvegicus Mus musculus Homo sapiens

PROVIDER: GSE61313 | GEO | 2014/09/11

SECONDARY ACCESSION(S): PRJNA260732

REPOSITORIES: GEO

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Project description:The HMC-1.1 and 1.2 human mast cell (huMC) lines are often employed in the study of attributes of neoplastic huMCs as found in patients with mastocytosis and their sensitivity to interventional drugs in vitro and in vivo. Both cell lines express mutated and constitutively active KIT, an essential growth factor receptor for huMC survival and function, with one KIT mutation in HMC-1.1 cells (V560G-KIT) and two in HMC-1.2 cells (D816V-KIT and V560G-KIT). D816V-KIT is commonly associated with systemic mastocytosis, while V560G-KIT appears more frequently in other human neoplasms. The functional consequences of the coexisting KIT mutations in HMC-1.2 cells are unknown. We used CRISPR/Cas9 engineering to reverse the V560G-KIT mutation in HMC-1.2 cells, resulting in a subline (HMC-1.3) with a single monoallelic D816V-KIT mutation. Transcriptome analyses of differentially expressed genes in HMC1.3 compared to HMC-1.2 predicted reduced activity in pathways involved in survival, cell-to-cell adhesion, and neoplasia, with differences in expression of molecular components and cell surface markers. Consistently, subcutaneous inoculation of HMC-1.3 into mice produced significantly smaller tumors than HMC-1.2 cells, and in colony assays, HMC-1.3 formed less numerous and smaller colonies than HMC-1.2 cells. However, in liquid culture conditions, the growth of HMC-1.2 and HMC-1.3 cells was comparable, albeit increased compared to HMC-1.1 cells. Phosphorylation levels of ERK1/2, AKT and STAT5, representing pathways associated with constitutive oncogenic KIT signaling, were also similar between HMC-1.2 and HMC-1.3 cells but increased compared to HMC-1.1 cells. Despite these similarities, survival of HMC-1.3 cells in liquid culture was diminished in response to various pharmacological inhibitors, including tyrosine kinase inhibitors used clinically for treatment of advanced systemic mastocytosis, and JAK2 and BCL2 inhibitors, making HMC-1.3 more susceptible to these drugs than HMC-1.2 cells. Our study reveals that the additional V560G-KIT variant in HMC-1.2 cells modifies transcriptional programs induced by D816V-KIT, confers a survival advantage, alters sensitivity to interventional drugs, and increases the tumorigenicity, suggesting that engineered huMCs with a single D816V-KIT variant may represent an improved preclinical model for mastocytosis.

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MicroRNA-7 modulates Rb1 and c-Myc expression in myeloid leukemias harboring c-Kit mutations

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