Activating mutations of the KIT receptor tyrosine kinase are frequently detected in core-binding factor AML and are associated with a greater risk of relapse.
This is typified by midostaurin, which has been approved by the US Food and Drug Administration for mutant FLT3-positive AML and for KITD816V-positive SM.
Permanently active KIT mutations lead these host cells to tumorigenesis, and to such diseases as mast cell leukemia (MCL), gastrointestinal stromal tumor (GIST), and acute myeloid leukemia (AML).
Bone marrow flowcytometric analysis showed myeloblast count of 74%, which expressed CD13, CD33, CD117 and HLA-DR. A diagnosis of AML (M2 type) was made and vulvar MS was the earliest symptom.
Our results proved that HOTAIR, miR-193a, and c-kit genes are independent prognostic predictors in 12p chromosomal associated AML; therefore it may represent a novel therapeutic application in AML in the future.
In our study, we compared the cytogenetic changes and gene mutations (NPM1, CEBPA, DNMT3A, FLT3-ITD, FLT3-TKD, and C-KIT) with clinical outcomes in 1132 patients with AML enrolled at our center over a 10-year period.
In this study, we evaluated the role of 5mC and 5hmC levels in HL60 AML cells and bone marrow samples from AML patients for KIT gene expression to analyze 5hmC level in AML pathogenesis.
A screen of two independent AML databases (AML<sup>databases</sup>) revealed remarkable similarities between KIT D816<sup>mut</sup>/CBF<sup>neg</sup> SM-AML and KIT D816<sup>mut</sup>/CBF<sup>neg</sup> AML<sup>databases</sup> (n = 69) with regard to KIT D816<sup>mut</sup> variant allele frequency, mutation profile, aberrant karyotype, and OS suggesting underlying SM in a significant proportion of AML<sup>databases</sup> patients.
We used the dual-luciferase and ChIP assays to demonstrate that the RUNX1-ETO protein epigenetically trans-activates c-KIT by binding to the c-KIT promoter and recruiting the histone acetyltransferase P300 to the c-KIT promoter, elucidating the mechanism of the abnormally increased c-KIT expression in t(8;21) AML patients.
In patients with t(8;21) AML, KIT mutational status was associated with miR-130a expression-with higher expression associated with KIT activating mutations.
Mechanistically, PPI significantly reduced the expression of C-KIT, another therapeutic target for AML with t(8;21), followed by inhibition of Akt signaling.
Like midostaurin, the metabolites potently inhibit mutant forms of FLT3 and KIT and several additional kinases that either are directly involved in the deregulated signaling pathways or have been implicated as playing a role in AML via stromal support, such as IGF1R, LYN, PDPK1, RET, SYK, TRKA, and VEGFR2.
The National Comprehensive Cancer Network (NCCN) defines the following types of acute myeloid leukemia (AML) as favorable-risk: acute promyelocytic leukemia with t(15;17) (APL); AML with core-binding factor (CBF) rearrangements, including t(8;21) and inv(16) or t(16;16) without mutations in KIT (CBF-KIT<sup>wt</sup>); and AML with normal cytogenetics and mutations in NPM1 (NPM1<sup>mut</sup>); or biallelic mutations in CEBPA (CEBPA<sup>mut/mut</sup>), without FLT3-ITD.
The prevalence and clinical relevance of KIT mutations in childhood core-binding factor (CBF) acute myeloid leukemia (AML) have not been well characterized.
Furthermore, we found that the role of IL1RAP is not restricted to the IL-1 receptor pathway, but that IL1RAP physically interacts with and mediates signaling and pro-proliferative effects through FLT3 and c-KIT, two receptor tyrosine kinases with known key roles in AML pathogenesis.
<b>Purpose:</b> c-KIT overexpression is well recognized in cancers such as gastrointestinal stromal tumors (GIST), small cell lung cancer (SCLC), melanoma, non-small cell lung cancer (NSCLC), and acute myelogenous leukemia (AML).
Furthermore, the investigation of lncRNAs in these prognostic modules suggested that an lncRNA (ZNF571-AS1) may be involved in AML via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway by regulating KIT and STAT5.