The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia
Year: 2011
Type: article
Study design: Observational Study
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.
Source: Blood
Authors: Alejandro Gutierrez, Alex Kentsis, Takaomi Sanda, Linda Holmfeldt, Shann-Ching Chen, Jianhua Zhang, Alexei Protopopov, Lynda Chin, Suzanne E. Dahlberg, Donna S. Neuberg, Lewis B. Silverman, Stuart S. Winter, Stephen P. Hunger, Stephen E. Sallan, Shan Zha, Frederick W. Alt, James R. Downing, Charles G. Mullighan, A. Thomas Look
Institutions: Boston Children's Hospital, Dana-Farber Cancer Institute, St. Jude Children's Research Hospital, University of New Mexico Health Sciences Center, Children's Hospital Colorado, University of Colorado Anschutz, University of Colorado Denver, Columbia University Irving Medical Center, Columbia University, Howard Hughes Medical Institute, Harvard University
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1399567684, G140054858, G1567188851, G2117365975, G2901481919, G3550411276, Support for Human Specimen Banking in NCI-Sponsored Clinical Trials-(CGB), G421865639, PEDIATRIC ONCOLOGY GROUP, Therapeutic Index of Acute Lymphoblastic Leukemia, G508888048, G524649420, G7478809817, G7569069942, PEDIATRIC ONCOLOGY GROUP STATISTICAL OFFICE, G7675368502, G806545856, G860380395, G997771125
OpenAlex ID: W2003913372