title: The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia.
abstract: The BCL11B transcription factor is required for normal T-cell development, and has recently been implicated in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) induced by TLX overexpression or Atm deficiency. To comprehensively assess the contribution of BCL11B inactivation to human T-ALL, we performed DNA copy number and sequencing analyses of T-ALL diagnostic specimens, revealing monoallelic BCL11B deletions or missense mutations in 9% (n = 10 of 117) of cases. Structural homology modeling revealed that several of the BCL11B mutations disrupted the structure of zinc finger domains required for this transcription factor to bind DNA. BCL11B haploinsufficiency occurred across each of the major molecular subtypes of T-ALL, including early T-cell precursor, HOXA-positive, LEF1-inactivated, and TAL1-positive subtypes, which have differentiation arrest at diverse stages of thymocyte development. Our findings provide compelling evidence that BCL11B is a haploinsufficient tumor suppressor that collaborates with all major T-ALL oncogenic lesions in human thymocyte transformation.
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors: Alejandro
authors: A
authors: Gutierrez
authors: Alex
authors: A
authors: Kentsis
authors: Takaomi
authors: T
authors: Sanda
authors: Linda
authors: L
authors: Holmfeldt
authors: Shann-Ching
authors: SC
authors: Chen
authors: Jianhua
authors: J
authors: Zhang
authors: Alexei
authors: A
authors: Protopopov
authors: Lynda
authors: L
authors: Chin
authors: Suzanne E
authors: SE
authors: Dahlberg
authors: Donna S
authors: DS
authors: Neuberg
authors: Lewis B
authors: LB
authors: Silverman
authors: Stuart S
authors: SS
authors: Winter
authors: Stephen P
authors: SP
authors: Hunger
authors: Stephen E
authors: SE
authors: Sallan
authors: Shan
authors: S
authors: Zha
authors: Frederick W
authors: FW
authors: Alt
authors: James R
authors: JR
authors: Downing
authors: Charles G
authors: CG
authors: Mullighan
authors: A Thomas
authors: AT
authors: Look
mesh_terms: D005260:Female; D017353:Gene Deletion; D057895:Haploinsufficiency; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D016335:Zinc Fingers / Q000235:genetics
chemical_list: C479740:BCL11B protein, human; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins