The proto-oncogene c-KIT encodes a receptor tyrosine kinase characterized by five extracellular immunoglobin-like domains, such as a single transmembrane helix, a cytoplasmic juxtamembrane domain (JMD), and a kinase domain. Mutations of c-KIT have been shown to occur in the extracellular portion of the receptor within exon 8, in the JMD domain within exon 11, and in the activation loop of the kinase domain within exon 17. All mutations led to the constitutive activation of the protein and promote development of human cancer, including hematological malignancies. Moreover, they have been frequently described to be associated with poor prognosis in adults with acute myeloid leukemia (AML) harboring aberrancies of the core binding factors (CBF). c-KIT mutations are also found in pediatric CBF-rearranged AML, but their incidence and prognostic impact are still debated. The AIEOP AML2001/02 protocol assigned patients with CBF rearrangements who reach complete remission (CR) at the end of the first course of induction therapy to the standard-risk (SR) group. These patients showed an incidence of relapse higher than expected (24%). New independent prognostic factors are thus desirable for improving the prognosis of this group of AML. In this study, we investigated the prognostic impact of c-KIT mutations.

Materials and Methods

We retrospectively analyzed the bone marrow of 49 and 30 patients carrying either the t(8;21) or inv(16)(p13;q22). Screening for mutations of c-KIT was assessed by PCR amplification followed by Sanger sequencing of the exons 8, 11 and 17. The prognostic impact was assessed through the calculation of the probability of event-free survival (EFS).


c-KIT mutations analyzed in the study are: the point mutation at D816 residue known to affect the activation loop of the kinase domain (exon 17); the internal tandem duplication located at exon 11, and small deletions or insertions, or combinations of deletions and insertions, of variable size at exon 8. The screening showed that 2/49 (4%) t(8;21) patients were positive for the point mutation affecting the codon D816V/Y; 2/49 (4%) for internal tandem duplication of exon 11, and 7/49 (14.3%) for small deletions and/or insertions of variable size in the extracellular portion of the receptor (exon 8). We found that the t(8;21) positive patients mutated for cKIT (18.3%) had a significant lower EFS (45.7%) than wild type patients (78.4%; p = 0.025). On the contrary, c-KIT mutations were rarely found in the cohort of inv(16) positive patients. In particular, 1/30 harbored the D816V, and 2/30 (6.6 %) had insertions at exon 8. No mutations at exon 11 were found.


c-KIT mutations are frequently found in t(8;21) postitive patients and they confer a worse prognosis. Targeted therapy with tyrosine kinase inhibitors may be considered as a new and promising therapeutic strategy for cKIT mutated patients in order to improve their outcome.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.