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Cancer Res. 2018 May 15;78(10):2669-2679. doi: 10.1158/0008-5472.CAN-17-3262. Epub 2018 Feb 28.

Loss of Pax5 Exploits Sca1-BCR-ABLp190 Susceptibility to Confer the Metabolic Shift Essential for pB-ALL.

Author information

1
Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain.
2
Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.
3
Department of Systems Biology, Beckman Research Institute, Monrovia, California.
4
Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Dusseldorf, Medical Faculty, Dusseldorf, Germany.
5
Institute of Medical Informatics, University of Muenster, Muenster, Germany.
6
Departamento de Anatomía Patológica, Universidad de Salamanca, Salamanca, Spain.
7
Servicio de Citometría and Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain.
8
Bioinformatics Unit, Cancer Research Center (CSIC-USAL) Salamanca, Spain.
9
Bioinformatics and Functional Genomics Research Group, Cancer Research Center (CSIC-USAL), Salamanca, Spain.
10
Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain.
11
Department of Systems Biology, Beckman Research Institute, Monrovia, California. Julia.Hauer@med.uni-duesseldorf.de muschen@coh.org Arndt.Borkhardt@med.uni-duesseldorf.de cvd@usal.es.
12
Institute of Medical Informatics, University of Muenster, Muenster, Germany. Julia.Hauer@med.uni-duesseldorf.de muschen@coh.org Arndt.Borkhardt@med.uni-duesseldorf.de cvd@usal.es.
13
Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain. Julia.Hauer@med.uni-duesseldorf.de muschen@coh.org Arndt.Borkhardt@med.uni-duesseldorf.de cvd@usal.es.

Abstract

Preleukemic clones carrying BCR-ABLp190 oncogenic lesions are found in neonatal cord blood, where the majority of preleukemic carriers do not convert into precursor B-cell acute lymphoblastic leukemia (pB-ALL). However, the critical question of how these preleukemic cells transform into pB-ALL remains undefined. Here, we model a BCR-ABLp190 preleukemic state and show that limiting BCR-ABLp190 expression to hematopoietic stem/progenitor cells (HS/PC) in mice (Sca1-BCR-ABLp190) causes pB-ALL at low penetrance, which resembles the human disease. pB-ALL blast cells were BCR-ABL-negative and transcriptionally similar to pro-B/pre-B cells, suggesting disease onset upon reduced Pax5 functionality. Consistent with this, double Sca1-BCR-ABLp190+Pax5+/- mice developed pB-ALL with shorter latencies, 90% incidence, and accumulation of genomic alterations in the remaining wild-type Pax5 allele. Mechanistically, the Pax5-deficient leukemic pro-B cells exhibited a metabolic switch toward increased glucose utilization and energy metabolism. Transcriptome analysis revealed that metabolic genes (IDH1, G6PC3, GAPDH, PGK1, MYC, ENO1, ACO1) were upregulated in Pax5-deficient leukemic cells, and a similar metabolic signature could be observed in human leukemia. Our studies unveil the first in vivo evidence that the combination between Sca1-BCR-ABLp190 and metabolic reprogramming imposed by reduced Pax5 expression is sufficient for pB-ALL development. These findings might help to prevent conversion of BCR-ABLp190 preleukemic cells.Significance: Loss of Pax5 drives metabolic reprogramming, which together with Sca1-restricted BCR-ABL expression enables leukemic transformation. Cancer Res; 78(10); 2669-79. ©2018 AACR.

PMID:
29490943
PMCID:
PMC6245574
[Available on 2019-05-15]
DOI:
10.1158/0008-5472.CAN-17-3262

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