Loss of Pax5 exploits Sca1-BCR-ABLp190 susceptibility to confer the metabolic shift essential for pB-ALL
- 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 towards 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.
Document Type: | Article |
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Language: | English |
Author: | Alberto Martín-Lorenzo, Franziska Auer, Lai N. Chan, Idoia García-Ramírez, Ines Gonzalez-Herrero, Guillermo Rodríguez-Hernández, Christoph Bartenhagen, Martin Dugas, Michael Gombert, Sebastian Ginzel, Oscar Blanco, Alberto Orfao, Diego Alonso-López, Javier de Las Rivas, Maria Begoña García-Cenador, Francisco Javier García Criado, Markus Müschen, Isidro Sánchez-García, Arndt Borkhardt, Carolina Vicente-Dueñas, Julia Hauer |
Parent Title (English): | Cancer Research |
Volume: | 78 |
Issue: | 10 |
First Page: | 2669 |
Last Page: | 2679 |
ISSN: | 1538-7445 |
DOI: | https://doi.org/10.1158/0008-5472.CAN-17-3262 |
PMID: | https://pubmed.ncbi.nlm.nih.gov/29490943 |
Publisher: | American Association for Cancer Research |
Date of first publication: | 2018/02/28 |
Departments, institutes and facilities: | Fachbereich Informatik |
Dewey Decimal Classification (DDC): | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Entry in this database: | 2018/03/27 |