title: Inactivation of the Cdkn2a locus cooperates with HMGA1 to drive T-cell leukemogenesis.
abstract: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia with high relapse rates compared to B-lineage ALL. We previously showed that HMGA1a transgenic mice develop aggressive T-ALL, indicating that HMGA1 causes leukemic transformation in vivo. HMGA1 is also highly expressed in embryonic stem cells, hematopoietic stem cells and diverse, refractory human cancers. Disruption of the CDKN2A tumor suppressor locus occurs in most cases of T-ALL and is thought to contribute to leukemic transformation. To determine whether loss of function of CDKN2A cooperates with HMGA1 in T-ALL, we crossed HMGA1a transgenics onto a Cdkn2a null background. We discovered that T-ALL is markedly accelerated in HMGA1a transgenic Cdkn2a null mice. In addition, these mice recapitulate salient clinical and pathologic features of human T-ALL. HMGA1 is also highly overexpressed in human T-ALL. These findings suggest that HMGA1 plays a causative role in T-ALL and could represent a rational therapeutic target.
authors: Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA,
authors: Francescopaolo
authors: F
authors: Di Cello
authors: Surajit
authors: S
authors: Dhara
authors: Alexandra C
authors: AC
authors: Hristov
authors: Jeanne
authors: J
authors: Kowalski
authors: Ossama
authors: O
authors: Elbahloul
authors: Joelle
authors: J
authors: Hillion
authors: Sujayita
authors: S
authors: Roy
authors: Jules P P
authors: JP
authors: Meijerink
authors: Stuart S
authors: SS
authors: Winter
authors: Richard S
authors: RS
authors: Larson
authors: David L
authors: DL
authors: Huso
authors: Linda
authors: L
authors: Resar
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004195:Disease Models, Animal; D004843:Epistasis, Genetic; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D056426:Genetic Loci; D025741:HMGA1a Protein / Q000235:genetics*; D006801:Humans; D016130:Immunophenotyping; D015458:Leukemia, T-Cell / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D025741:HMGA1a Protein