Expression and functional role of the proto-oncogene c-kit in acute myeloblastic leukemia cells

Abstract

The c-kit proto-oncogene encodes a receptor tyrosine kinase that is thought to play an important role in hematopoiesis. In a series of human acute myeloblastic leukemia (AML), the expression of the c-kit proto-oncogene and its product was studied by means of Northern blot and immunoblot analyses. The c-kit mRNA was expressed in 20 of 25 cases of AML, and in those cases the product of the c-kit proto-oncogene was detected by immunoblotting with anti-c-kit antibody. The expression of c-kit transcripts and protein was barely detectable in normal bone marrow cells as a control. The expression of c-kit transcript did not correlate with the French-American-British classification nor clinical manifestations. In 6 of 11 cases that expressed c-kit product, AML cells were found to proliferate in response to recombinant human stem cell factor (rhSCF), the ligand for c-kit, and the synergistic stimulation of AML cells was observed by rhSCF and granulocyte- macrophage colony-stimulating factor. Immunoblotting with anti- phosphotyrosine antibody showed that the c-kit receptor protein was detectably phosphorylated in 7 of 12 cases tested before the stimulation with rhSCF, while the rhSCF treatment resulted in an increased tyrosine phosphorylation of c-kit in AML cells. These results indicate that c-kit proto-oncogene is expressed in most cases of AML and is functional in terms of supporting proliferation.

CRISPR Gene Editing of Murine Blood Stem and Progenitor Cells Induces MLL-AF9 Chromosomal Translocation and MLL-AF9 Leukaemogenesis

“…Normal primary HSPC cells have limited growth potential in vitro, which showed increased colony growth and number when expressing MA9. Increased clonogenicity is associated with increased c-Kit expression, a cell surface marker found in myeloblasts in up to 80% of AML cases [54]. C-Kit expression has also been strongly associated with poor prognoses in other instances of chromosomal translocations such as t(8;21) [55].…”

Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia

“…It has been established that numerous malignancies such as mastocytosis, gastrointestinal tumours, melanomas and human mast cell leukaemia are the result of KIT mutations [ 61 , 62 , 63 , 64 ]. Almost 80% of AML cases have been found to have KIT proto-oncogene expression and support cell proliferation [ 65 ]. KIT has an additional role of improving the fibronectin attachment of the AML cells, leading to proliferative and antiapoptotic signals [ 66 ].…”

The Dynamic Interface Between the Bone Marrow Vascular Niche and Hematopoietic Stem Cells in Myeloid Malignancy

“…It is approved for renal carcinoma and soft tissue sarcoma, in which it impairs perfusion of the solid tumor. Pazopanib’s kinase selectivity profile suggests multiple concurrent potential anti-leukemic mechanisms, given the dominant expression of KIT (CD117) on blasts from ∼60–70% of AMLs, and expression of PDGFR-α and –β in 45% and > 90% of AMLs, respectively, in addition to any VEGFR-targeting anti-angiogenic effect ( Ikeda et al, 1991 ; Foss et al, 2001 ). Having observed low nanomolar in vitro cytotoxicity in AML cell lines, the German phase 2 PazoAML trial reported modest efficacy as monotherapy in a relapsed/refractory AML cohort, including two partial remissions (PR) with > 50% blast reduction ( Kessler et al, 2019 ).…”