Analysis Of C-KIT Gene Mutations In Acute Myloid Leukemia M2 With T(8; 21)

【Background and Objectives】C-KIT proto-oncogene encodes for a classⅢtransmembrane receptor tyrosine kinase(stem cell factor receptor). The mutated C-KIT gene results in continuous activating of C-KIT receptor, and confers proliferative and survival advantage to hematopoietic progenitors. C-KIT exon 8 and 17 mutations were identified as the most frequent gene mutation in acute myeloid leukemia (AML) with core binding factor(CBF-AML). However, there were not any reports on clinical research in our country so far. Objectives: (1) To evaluate the prevalence and clinical characteristics of mutated C-KIT(mutKIT) in 78 adult AML-M2 patients with t(8;21). (2) To evaluate correlation of JAK2V617F mutation and C-KIT gene mutations in these 78 adult AMLs with t(8;21) and analyzed theirs prognostic impact.【Patients and Methods】78 adult patients (range, 14-77 years) were newly diagnosed AML-M2 with t(8;21) at Jiangsu Institute of Hematology from February 2004 to January 2008. The diagnosis was based on the morphology, immunophenotype, karyotype and fusion gene of cells in bone marrow. (1) Genomic DNAs from 78 AML-M2 patients with t(8;21) were screened for mutated C-KIT(mutKIT) in exon 8 and 17 by PCR and sequencing. (2) Follow up the clinical and lab datas of these cases, then summarize the characteristics. (3) Estimate the clinical prognosis based on the response to therapies of inpatients. (4) JAK2V617 mutation screening was processed through allele-specific PCR.【Results】Among 78 AML patients with t(8;21), 27(34.6%) had mutKIT(21 with mutkIT17, 5 with mutKIT8, and 1 with mutKIT17 and mutKIT8). C-KIT mutations at codon D816 were more frequent(15/27). Sequence analysis of 27 mutKIT cases revealed a novel mutation in C-KIT exon 17 that led to the deletion of an aspartate and insertion of an amino acid triplet valine-valine-alanine at codon 816. Peripheral WBC count was higher for mutKIT patients(P<0.05) compared with wide-type C-KIT(wtKIT) patients. The hemoglobin level, platelet counts, percentage of blast cell in bone marrow, level of CD117 expression, age of onset and complete remission(CR) rate of patients with mutKIT and wtKIT were similar. The continuous CR (CCR) rate of 2 years was lower for patients with mutKIT(23.9% vs 55.6%, P<0.05) and those with mutKIT17(17.3% vs 55.6%, P<0.05) compared with wtKIT patients. However, mutKIT did not influence overall survival(OS), but mutKIT17 predicted worse OS.Among these 78 patients, 6(7.7%) cases had JAK2V617F, and none had both mutKIT and JAK2V617F. Peripheral WBC count was higher for mutKIT/JAK2V617F patients (P<0.05) compared with wide-type C-KIT/JAK2 (wtKIT/JAK2) patients. CR rate of these two groups was similar, but the CCR rate of 2 years was lower for patients with mutKIT/JAK2V617F (26.7% vs 56.1%, P<0.05) compared with wtKIT/JAK2 patients. However, there was no significant difference in OS between mutKIT/JAK2V617F and wtKIT/JAK2. Due to only 6 patients with JAK2V617F mutation, these data were not statistically analyzed respectively.【Conclusions】In AML-M2 with t(8;21), mutKIT correlates with higher peripheral WBC count. The mutKIT, and especially mutKIT17, confers higher relapse risk and predicts poor prognosis. Occurrence of cooperating mutations of PTK family are common in AML-M2 patients with t(8;21), especially such as C-KIT mutation, and are associated with higher WBC count. Generally , the occurrence of gene mutations of PTK family was mutually exclusive. These mutations predict poor prognosis and could be an additional genetic events leading to the development of AML-M2. However, the prognostic implications of JAK2V617F are still unclear due to the small number of samples. So, it would be significant to screen for these gene mutations at diagnosis for clinical prognosis and targeted therapy.