Inactivation of the Cdkn2a locus cooperates with HMGA1 to drive T-cell leukemogenesis

被引：19

作者：

Di Cello, Francescopaolo ^{[1
,2
]}

Dhara, Surajit ^{[1
,2
]}

Hristov, Alexandra C. ^{[3
]}

Kowalski, Jeanne ^{[4
,5
]}

Elbahloul, Ossama ^{[1
,2
,6
]}

Hillion, Joelle ^{[1
,2
]}

Roy, Sujayita ^{[1
,2
]}

Meijerink, Jules P. P. ^{[8
]}

Winter, Stuart S. ^{[9
]}

Larson, Richard S. ^{[10
]}

Huso, David L. ^{[3
,5
,7
]}

Resar, Linda ^{[1
,2
,5
,6
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Div Hematol, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Sch Med, Dept Biostat, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA

[6] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA

[7] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD 21205 USA

[8] Erasmus MC Sophia Childrens Hosp, Dept Pediat Oncol Hematol, Rotterdam, Netherlands

[9] Univ New Mexico, Dept Pediat, Albuquerque, NM 87131 USA

[10] Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA

来源：

LEUKEMIA & LYMPHOMA | 2013年 / 54卷 / 08期

关键词：

T-cell acute leukemia; HMGA1; mouse models; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; GENE-EXPRESSION; TRANSGENIC MICE; STEM-CELL; UTERINE TUMORIGENESIS; TUMOR SUPPRESSION; LUNG-CANCER; TARGET; I/Y;

D O I：

10.3109/10428194.2013.764422

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：1762 / 1768

页数：7

共 52 条

[1] Microarray-based classification of a consecutive series of 121 childhood acute leukemias: prediction of leukemic and genetic subtype as well as of minimal residual disease status [J].

Andersson, A. ;

Ritz, C. ;

Lindgren, D. ;

Eden, P. ;

Lassen, C. ;

Heldrup, J. ;

Olofsson, T. ;

Rade, J. ;

Fontes, M. ;

Porwit-MacDonald, A. ;

Behrendtz, M. ;

Hoglund, M. ;

Johansson, B. ;

Fioretos, T. .

LEUKEMIA, 2007, 21 (06) :1198-1203

[2] Loss of Hmga1 gene function affects embryonic stem cell lymphohematopoietic differentiation [J].

Battista, S ;

Pentimalli, F ;

Baldassarre, G ;

Fedele, M ;

Fidanza, V ;

Croce, CM ;

Fusco, A .

FASEB JOURNAL, 2003, 17 (09) :1496-+

[3] FR900482 class of anti-tumor drugs cross-links oncoprotein HMG I/Y to DNA in vivo [J].

Beckerbauer, L ;

Tepe, JJ ;

Cullison, J ;

Reeves, R ;

Williams, RM .

CHEMISTRY & BIOLOGY, 2000, 7 (10) :805-812

[4] HMGA1 Induces Intestinal Polyposis in Transgenic Mice and Drives Tumor Progression and Stem Cell Properties in Colon Cancer Cells [J].

Belton, Amy ;

Gabrovsky, Alexander ;

Bae, Young Kyung ;

Reeves, Ray ;

Iacobuzio-Donahue, Christine ;

Huso, David L. ;

Resar, Linda M. S. .

PLOS ONE, 2012, 7 (01)

[5] An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors [J].

Ben-Porath, Ittai ;

Thomson, Matthew W. ;

Carey, Vincent J. ;

Ge, Ruping ;

Bell, George W. ;

Regev, Aviv ;

Weinberg, Robert A. .

NATURE GENETICS, 2008, 40 (05) :499-507

[6] Multicenter, Phase II Study of Decitabine for the First-Line Treatment of Older Patients With Acute Myeloid Leukemia [J].

Cashen, Amanda F. ;

Schiller, Gary J. ;

O'Donnell, Margaret R. ;

DiPersio, John F. .

JOURNAL OF CLINICAL ONCOLOGY, 2010, 28 (04) :556-561

[7] Efficient human iPS cell derivation by a non-integrating plasmid from blood cells with unique epigenetic and gene expression signatures [J].

Chou, Bin-Kuan ;

Mali, Prashant ;

Huang, Xiaosong ;

Ye, Zhaohui ;

Dowey, Sarah N. ;

Resar, Linda M. S. ;

Zou, Chunlin ;

Zhang, Y. Alex ;

Tong, Jay ;

Cheng, Linzhao .

CELL RESEARCH, 2011, 21 (03) :518-529

[8] Antagonism of Myc functions by Arf [J].

Cleveland, JL ;

Sherr, CJ .

CANCER CELL, 2004, 6 (04) :309-311

[9] Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL [J].

Della Gatta, Giusy ;

Palomero, Teresa ;

Perez-Garcia, Arianne ;

Ambesi-Impiombato, Alberto ;

Bansal, Mukesh ;

Carpenter, Zachary W. ;

De Keersmaecker, Kim ;

Sole, Xavier ;

Xu, Luyao ;

Paietta, Elisabeth ;

Racevskis, Janis ;

Wiernik, Peter H. ;

Rowe, Jacob M. ;

Meijerink, Jules P. ;

Califano, Andrea ;

Ferrando, Adolfo A. .

NATURE MEDICINE, 2012, 18 (03) :436-U198

[10] Cyclooxygenase inhibitors block uterine tumorigenesis in HMGA1a transgenic mice and human xenografts [J].

Di Cello, Francescopaolo ;

Hillion, Joelle ;

Kowalski, Jeanne ;

Ronnett, Brigitte M. ;

Aderinto, Abimbola ;

Huso, David L. ;

Resar, Linda M. S. .

MOLECULAR CANCER THERAPEUTICS, 2008, 7 (07) :2090-2095

← 1 2 3 4 5 6 →