title: Modeling interactions between leukemia-specific chromosomal changes, somatic mutations, and gene expression patterns during progression of core-binding factor leukemias.
abstract: In cancer genomes, changes observed during tumor progression can be difficult to separate from nonspecific accumulation of cytogenetic changes due to cancer-associated genetic instability. We studied genetic changes occurring over time in cancers presenting with a relatively simple karyotype, namely two related core-binding factor (CBF) acute myeloid leukemias (AMLs), to assess how specific chromosomal changes are selected based on tumor subtype and acquired somatic mutations. Expression profiles for DNA replication/repair genes and the mutation status of KRAS, NRAS, FLT3, and KIT were compared with the karyotypic changes at diagnosis and relapse(s) in 94 cases of inv(16)(p13.1q22)-AML and 82 cases of t(8;21)(q22;q22)-AML. The majority of both AML types demonstrated a simple aneuploid pattern of cytogenetic progression, with highly distinctive patterns of chromosome copy number changes, such as +22 and +13 exclusively in inv(16)-AML and -Y and -X in t(8;21)-AML. Selection of certain cytogenetic changes correlated with particular somatic mutations, such as +8 with RAS mutation, and absence of kinase pathway mutations in t(8;21)-AML with localized deletions at chromosome band 9q22. Alterations in transcript levels of mitotic spindle kinases such as CHEK1, AURKA, and AURKB were associated with the aneuploid progression pattern, particularly in t(8;21) cases. Despite the similarity in the initiating genetics of the two CBF AML types, highly tumor-specific patterns of limited aneuploidy are noted that persist and continue to accumulate at relapse. Thus, activation of genetic instability, possibly through mitotic spindle dysregulation, leads rapidly to the selection of advantageous single chromosome aneuploidy.
authors.affiliation: Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. dajones@mdanderson.org
authors.forename: Dan
authors.initials: D
authors.lastname: Jones
authors.forename: Hui
authors.initials: H
authors.lastname: Yao
authors.forename: Angela
authors.initials: A
authors.lastname: Romans
authors.forename: Caroline
authors.initials: C
authors.lastname: Dando
authors.forename: Sherry
authors.initials: S
authors.lastname: Pierce
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.forename: Amy
authors.initials: A
authors.lastname: Hamilton
authors.forename: Carlos
authors.initials: C
authors.lastname: Bueso-Ramos
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
mesh_terms: D001854:Bone Marrow Cells / Q000473:pathology; D002877:Chromosomes, Human / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D050660:Core Binding Factors / Q000235:genetics*; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D012008:Recurrence; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D050660:Core Binding Factors