title: An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia.
abstract: To define the mutation spectrum in non-Down syndrome acute megakaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL samples. Our analysis identified a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)) in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis.
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Tanja A
authors.initials: TA
authors.lastname: Gruber
authors.forename: Amanda
authors.initials: A
authors.lastname: Larson Gedman
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.forename: Cary S
authors.initials: CS
authors.lastname: Koss
authors.forename: Suresh
authors.initials: S
authors.lastname: Marada
authors.forename: Huy Q
authors.initials: HQ
authors.lastname: Ta
authors.forename: Shann-Ching
authors.initials: SC
authors.lastname: Chen
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Su
authors.forename: Stacey K
authors.initials: SK
authors.lastname: Ogden
authors.forename: Jinjun
authors.initials: J
authors.lastname: Dang
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.forename: Vedant
authors.initials: V
authors.lastname: Gupta
authors.forename: Anna K
authors.initials: AK
authors.lastname: Andersson
authors.forename: Stanley
authors.initials: S
authors.lastname: Pounds
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: John
authors.initials: J
authors.lastname: Easton
authors.forename: Michael I
authors.initials: MI
authors.lastname: Barbato
authors.forename: Heather L
authors.initials: HL
authors.lastname: Mulder
authors.forename: Jayanthi
authors.initials: J
authors.lastname: Manne
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Rusch
authors.forename: Swati
authors.initials: S
authors.lastname: Ranade
authors.forename: Ramapriya
authors.initials: R
authors.lastname: Ganti
authors.forename: Matthew
authors.initials: M
authors.lastname: Parker
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Ina
authors.initials: I
authors.lastname: Radtke
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cazzaniga
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
authors.forename: Paola
authors.initials: P
authors.lastname: Ballerini
authors.forename: Sheila
authors.initials: S
authors.lastname: Shurtleff
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tomizawa
authors.forename: Souichi
authors.initials: S
authors.lastname: Adachi
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Akio
authors.initials: A
authors.lastname: Tawa
authors.forename: Lee-Yung
authors.initials: LY
authors.lastname: Shih
authors.forename: Der-Cherng
authors.initials: DC
authors.lastname: Liang
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Rubnitz
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002648:Child; D007446:Chromosome Inversion; D002885:Chromosomes, Human, Pair 16; D004330:Drosophila / Q000235:genetics / Q000254:growth & development; D020869:Gene Expression Profiling; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D007947:Leukemia, Megakaryoblastic, Acute / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D011379:Prognosis; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D019485:Bone Morphogenetic Proteins; C115744:CBFA2T3 protein, human; C577580:CBFA2T3-GLIS2 fusion protein, human; C447919:GLIS2 protein, human; D051741:Kruppel-Like Transcription Factors; D015514:Oncogene Proteins, Fusion; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins