title: Mutations in the CCND1 and CCND2 genes are frequent events in adult patients with t(8;21)(q22;q22) acute myeloid leukemia.
abstract: 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 1 (0.9%) patient with inv(16). In contrast, CCND1 and CCND2 mutations were detected in only 11 (0.77%) of 1426 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.
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: A-K
authors.initials: AK
authors.lastname: Eisfeld
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.|Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kohlschmidt
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Schwind
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.|Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Nicolet
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Blachly
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Orwick
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: C
authors.initials: C
authors.lastname: Shah
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bainazar
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: K W
authors.initials: KW
authors.lastname: Kroll
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Walker
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Carroll
authors.affiliation: Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Powell
authors.affiliation: Dana-Farber/Partners CancerCare, Boston, MA, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Stone
authors.affiliation: Monter Cancer Center, Hofstra North Shore-Long Island Jewish School of Medicine, Lake Success, NY, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Kolitz
authors.affiliation: Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Baer
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: A
authors.identifier: 0000-0001-9345-9248
authors.initials: A
authors.lastname: de la Chapelle
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: K
authors.initials: K
authors.lastname: Mrózek
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Bloomfield
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D019938:Cyclin D1 / Q000235:genetics*; D056742:Cyclin D2 / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate; D014178:Translocation, Genetic; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; C080336:CCND2 protein, human; D056742:Cyclin D2; D019938:Cyclin D1