• What is KIT?
  • KIT in Acute Myeloid Leukemia
  • KIT c.2446_2447delGAinsAT (D816I)
  • Clinical Trials

KIT

KIT (also called CD117) is a receptor tyrosine kinase (RTK) expressed on a wide variety of cell types. The ligand for KIT is stem cell factor (SCF). The binding of SCF to the extracellular domain of KIT induces receptor dimerization and activation of downstream signaling pathways, including the PI3K-AKT-mTOR pathway, the RAS-RAF-MEK-ERK pathway, and the signal transducer and activator of transcription 3 (acute-phase response factor), or STAT3, pathway, all of which are involved in mediating pro-growth and pro-survival signals within the cell (Figure 1).

Mutant KIT has been implicated in the pathogenesis of several cancers including melanoma, acute leukemia, and gastrointestinal stromal tumor (GIST; Heinrich et al. 2003; Hirota et al. 1998).

The discovery of KIT mutations revolutionized the treatment of GISTs. The use of imatinib mesylate (Gleevec), an oral KIT inhibitor leads to rapid, substantial, and durable tumor responses (Demetri et al. 2002). Not all KIT mutations are associated with equal sensitivity to imatinib (Heinrich et al. 2008); some are more sensitive to second-generation KIT inhibitors.

kit-signaling.png

Figure 1.
Schematic of KIT signaling pathways. The binding of SCF, to the KIT receptor tyrosine kinase results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK), the PI3K pathway (PI3K-AKT-mTOR), and the STAT3 pathway. The letter "K" within the schema denotes the tyrosine kinase domain.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Jeff Sosman, M.D., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., J. Sosman, W. Pao. 2015. KIT. My Cancer Genome https://www.padiracinnovation.org/content/disease/acute-myeloid-leukemia/kit/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

KIT in Acute Myeloid Leukemia

KIT is mutated in 8.0% of acute myeloid leukemia (COSMIC). Oncogenic KIT mutations occur primarily in core binding factor (CBF) AML (Ashman and Griffith 2013). KIT mutations occur primarily in exon 17 and affect the activation loop of the kinase domain (Ashman and Griffith 2013; Malaise et al. 2009). These changes result in improved survival and growth of tumor cells (Ashman and Griffith 2013). KIT mutations fall into class I of the “two-hit” theory of leukemogenesis (Naoe and Kiyoi 2013). ​

Contributors: Scott Wheeler, Ph.D. (through June 2014), Adam Seegmiller, M.D., Ph.D., Cindy L. Vnencak-Jones, Ph.D.

Suggested Citation: Wheeler, S., A. Seegmiller, C. Vnencak-Jones. 2013. KIT in Acute Myeloid Leukemia. My Cancer Genome https://www.padiracinnovation.org/content/disease/acute-myeloid-leukemia/kit/ (Updated September 9).

Last Updated: September 9, 2013

KIT c.2446_2447delGAinsAT (D816I) Mutation in Acute Myeloid Leukemia

Properties
Location of mutation Kinase domain (exon 17)
Frequency of KIT mutations in AML 8.0% (COSMIC)
Frequency of KIT D816I mutation in KIT-mutated AML < 1% (COSMIC)
Implications for Targeted Therapeutics
Response to FLT3 inhibitors Unknown at this time
Response to MEK inhibitors Unknown at this time
Response to JAK2 inhibitors Unknown at this time
Response to KIT inhibitors Unknown at this timea

The D816I mutation results in an amino acid substitution at position 816 in KIT, from an aspartic acid (D) to an isoleucine (I). This mutation is associated with intermediate prognosis in AML in patients with t(8;21), inv(16), or t(16;16) karyotype (NCCN 2012). In patients without KIT mutations, t(8;21), inv(16), and t(16;16) are associated with favorable prognosis (NCCN 2012; NCI 2013).

a Available evidence indicates that KIT D816 mutations may be resistant to KIT inhibition (Gajiwala et al. 2009; Smith and Shah 2013).

KIT D816I

Figure 1. Schematic of KIT. Domains encoded by various exons are shown. NOTE: JM = juxtamembrane domain; TM = transmembrane domain.

Contributors: Scott Wheeler, Ph.D. (through June 2014), Adam Seegmiller, M.D., Ph.D., Cindy L. Vnencak-Jones, Ph.D.

Suggested Citation: Wheeler, S., A. Seegmiller, C. Vnencak-Jones. 2014. KIT c.2446_2447delGAinsAT (D816I) Mutation in Acute Myeloid Leukemia. My Cancer Genome https://www.padiracinnovation.org/content/disease/acute-myeloid-leukemia/kit/276/ (Updated January 23).

Last Updated: January 23, 2014

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