Mutations in the CCND1and CCND2genes are frequent events in adult patients with t(8;21)(q22;q22) acute myeloid leukemia

Core-binding factor acute myeloid leukemia (CBF-AML) is defined by the presence of either t(8;21)(q22;q22)/RUNX1-RUNX1T1or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11. The resulting fusion genes require a ‘second hit’ to initiate leukemogenesis. Mutation assessment of 177 adults with CBF-AML, including 68 with t(8;21) and 109 with inv(16)/t(16;16), identified not only mutations well known in CBF-AML but also mutations in the CCND1and CCND2genes, which represent novel frequent molecular alterations in AML with t(8;21). Altogether, CCND1(n=2) and CCND2(n=8) mutations were detected in 10 (15%) patients with t(8;21) in our cohort. A single CCND2mutation was also found in 1 (0.9%) patient with inv(16). In contrast, CCND1and CCND2mutations were detected in only 11 (0.77%) of 1426 non-CBF-AML patients. All CCND2mutations cluster around the highly conserved amino-acid residue threonine 280 (Thr280). We show that Thr280Ala-mutated CCND2 leads to increased phosphorylation of the retinoblastoma protein, thereby causing significant cell cycle changes and increased proliferation of AML cell lines. The identification of CCND1and CCND2mutations as frequent mutational events in t(8;21) AML may provide further justification for cell cycle-directed therapy in this disease.