Loss of Pax5 Exploits Sca1-BCR-ABL(p190) Susceptibility to Confer the Metabolic Shift Essential for pB-ALL
Summary
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. ©2018 American Association for Cancer Research.
| Authors | Martín-Lorenzo A, Auer F, Chan LN, García-Ramírez I, González-Herrero I, Rodríguez-Hernández G, Bartenhagen C, Dugas M, Gombert M, Ginzel S, Blanco O, Orfao A, Alonso-López D, Rivas JL, García-Cenador MB, García-Criado FJ, Müschen M, Sánchez-García I, Borkhardt A, Vicente-Dueñas C, Hauer J |
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| Journal | Cancer research |
| Publication Date | 2018 May 15;78(10):2669-2679 |
| PubMed | 29490943 |
| PubMed Central | PMC6245574 |
| DOI | 10.1158/0008-5472.can-17-3262 |