Different Cooperating Mutation Patterns of Receptor Tyrosine Kinases/Ras/JAK2 between De Novo AML1-ETO and CBFβ-MYH11 Acute Myeloid Leukemia.

Abstract

Background. Two-hit model of leukemogenesis has been proposed for AML; class I mutations that drive proliferation and survival, and class II mutations that block differentiation. Core-binding factor (CBF) AML consists of AML with AML1-ETO and AML with CBFβ-MYH11, that are class II mutations.Aim. We sought1.to determine the frequencies of cooperating mutations of class I including receptor tyrosine kinases (RTK)/Ras/JAK2 signaling pathways in CBF-AML, and2.to compare the patterns of cooperating mutations between AML with AML1-ETO and AML with CBFβ-MYH11.Patients and methods. By RT-PCR analysis, 130 adult and 45 children were identified to have CBF-AML, 129 with AML1-ETO and 46 with CBFβ-MYH11. Bone marrow samples at diagnosis were analyzed for FLT3-LM, FLT3-TKD, c-KIT, c-FMS, N-ras, K-ras and JAK2 mutations.Results. Sixty-six of 129 patients (51.2%) with AML1-ETO had RTK/Ras/JAK2 mutations compared with 30 of 46 patients (65.2%) with CBFβ-MYH11 (p=0.121). The frequencies of RTK/Ras/JAK2 mutations in 129 AML1-ETO AML were 3.9% (n=5) for FLT3-LM, 6.2% (n=8) for FLT3-TKD, 2.3% (n=3) for N-ras, 3.9% (n=5) for K-ras, 35.7% (n=46) for c-KIT, and1.6% (n=2) for JAK2 mutation. The frequencies of RTK/Ras/JAK2 mutations in 46 CBFβ-MYH11 AML were 2.2% (n=1) for FLT3-LM, 19.6% (n=9) for FLT3-TKD, 21.7% (n=10) for N-ras, 23.9% (n=11) for c-KIT, and none for K-ras or JAK2 mutations. No c-FMS mutations were detected in both subtypes of CBF-AML. All RTK/Ras/JAK2 mutations were mutually exclusive except three, one each with N-ras and K-ras mutations, FLT3-TKD and c-KIT mutations, c-KIT and JAK2 mutations, respectively. Patients with CBFβ-MYH11 had a significantly higher frequency of FLT3-TKD and N-ras mutations than patients with AML1-ETO (p=0.017 for FLT3-TKD, and p<0.001 for N-ras). Taken together, c-KIT mutations accounted for 32.6% in CBF-AML, the frequency of c-KIT mutations in patients with AML1-ETO was significantly higher than that of CBFβ-MYH11 subtype. Of the 46 patients with AML1-ETO and c-KIT mutations, 34 had mutations located at kinase domain (exon 17), 7 in exon 8, 1 in exon 9, and 4 in exon 11. Of the 11 patients with CBFβ-MYH11 and c-KIT mutations, 5 had mutations in exon 8, 2 in exon 11 and 4 in exon 17. Patients with AML1-ETO were more frequently associated with c-KIT mutations at kinase domain compared with patients with CBFβ-MYH11 (p=0.031), whereas those with CBFβ-MYH11 had a higher frequency of c-KIT mutations in exon 8 than patients with AML1-ETO (p=0.042).Conclusion. Our results showed that occurrence of cooperating mutations of RTK/Ras/JAK2 pathways are common in patients with CBF-AML, but the patterns of mutations were different between AML1-ETO and CBFβ-MYH11 subtypes.