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.

Keywords::

• T-cell acute leukemia
• HMGA1
• mouse models

Potential conflict of interest:

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

This study was supported by NIH grant R01 CA092339 (to L.R.), Leukemia & Lymphoma Scholar Award 1694-06 (to L.R.), Alex's Lemonade Stand Foundation Awards (to L.R. and J.H.), St. Baldrick's Foundation for Childhood Cancer (to L.R.), Association for Research on Childhood Cancer (to L.R.), the J. P. McCarthy Fund (to L.R.) and the Maryland Stem Cell Research Fund (to L.R. and J.H.).