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Título: | Loss of Pax5 exploits sca1-BCR-ABLp190 susceptibility to confer the metabolic shift essential for pB-ALL |
Autor: | Martín-Lorenzo, Alberto CSIC ORCID; Auer, Franziska; Chan, Lai N.; García-Ramírez, Idoia CSIC; González-Herrero, Inés CSIC ORCID; Rodríguez-Hernández, Guillermo CSIC ORCID ; Bartenhagen, Christoph; Dugas, Martin; Gombert, Michael; Ginzel, Sebastian; Blanco, Óscar; Orfao, Alberto CSIC ORCID ; Alonso-López, D. CSIC ORCID; Rivas, Javier de las ; García-Cenador, Begoña; García-Criado, Francisco Javier; Müschen, Markus; Sánchez García, Isidro CSIC ORCID ; Borkhardt, Arndt; Vicente-Dueñas, Carolina CSIC ORCID; Hauer, Julia | Fecha de publicación: | may-2018 | Editor: | American Association for Cancer Research | Citación: | Cancer Research 78(10): 2669-2679 (2018) | Resumen: | 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. | Versión del editor: | http://dx.doi.org/10.1158/0008-5472.CAN-17-3262 | URI: | http://hdl.handle.net/10261/245144 | DOI: | 10.1158/0008-5472.CAN-17-3262 | ISSN: | 0008-5472 | E-ISSN: | 1538-7445 |
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