Mutations in the CCND1 and CCND2 genes are frequent events in adult patients with t(8;21)(q22;q22) acute myeloid leukemia
Autor: | Jonathan E. Kolitz, Jessica Kohlschmidt, Christopher J. Walker, A-K Eisfeld, Richard Stone, Maria R. Baer, Shelley Orwick, James S. Blachly, John C. Byrd, A de la Chapelle, Deedra Nicolet, Clara D. Bloomfield, Maryam Bainazar, Karl Kroll, Andrew J. Carroll, Chandni Shah, Sebastian Schwind, Bayard L. Powell, Krzysztof Mrózek |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Adult Male congenital hereditary and neonatal diseases and abnormalities Cancer Research medicine.medical_specialty endocrine system Adolescent Chromosomes Human Pair 21 Biology Translocation Genetic Article Fusion gene 03 medical and health sciences Young Adult Internal medicine hemic and lymphatic diseases otorhinolaryngologic diseases medicine Biomarkers Tumor Cyclin D2 Humans Cyclin D1 neoplasms Aged Neoplasm Staging Hematology Myeloid leukemia Middle Aged medicine.disease Prognosis Lymphoma Survival Rate Haematopoiesis Leukemia Leukemia Myeloid Acute 030104 developmental biology Oncology Immunology Mutation Female Stem cell T(8 21)(q22 q22) Chromosomes Human Pair 8 Follow-Up Studies |
Zdroj: | Leukemia. 31(6) |
ISSN: | 1476-5551 |
Popis: | Core-binding factor acute myeloid leukemia (CBF-AML) is defined by the presence of either t(8;21)(q22;q22)/RUNX1-RUNX1T1 or 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 CCND1 and CCND2 genes, 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 CCND2 mutation was also found in one (0.9%) patient with inv(16). In contrast, CCND1 and CCND2 mutations were detected in only 11 (0.77%) of 1,426 non-CBF-AML patients. All CCND2 mutations 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 CCND1 and CCND2 mutations as frequent mutational events in t(8;21) AML may provide further justification for cell cycle-directed therapy in this disease. |
Databáze: | OpenAIRE |
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