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Título
Loss of Pax5 exploits sca1-BCR-ABLp190 susceptibility to confer the metabolic shift essential for pB-ALL
Autor(es)
Materia
Acute lymphoblastic-leukemia
Gene-expression
BCR-ABL
Fusion genes
Stem-cells
Adult
Mice
Differentiation
Repression
Enrichment
Clasificación UNESCO
3201.01 Oncología
Fecha de publicación
2018
Editor
American Association for Cancer Research
Citación
Martín-Lorenzo, A., Auer, F., Chan, L. N., 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, J. D. L., García-Cenador, M. B., García-Criado, F. J., Müschen, M., Sánchez-García, I., Borkhardt, A., … Hauer, J. (2018). Loss of Pax5 Exploits Sca1-BCR-ABLp190 Susceptibility to Confer the Metabolic Shift Essential for pB-ALL. Cancer Research, 78(10), 2669-2679. https://doi.org/10.1158/0008-5472.CAN-17-3262
Resumen
[EN]Preleukemic clones carrying BCR-ABL(P190) 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-ABL(P190) preleukemic state and show that limiting BCR-ABL(P190) expression to hematopoietic stem/progenitor cells (HS/PC) in mice (Sca1-BCR-ABL(P190)) 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- ABI(P190) +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-ABL(P190) and metabolic reprogramming imposed by reduced Pax5 expression is sufficient for pR-All. development. These findings might help to prevent conversion of BCR-ABL(P190) preleukemic cells.
Significance: Loss of Pax5 drives metabolic reprogramming, which together with Scat-restricted BCR-ABL expression enables leukemic transformation. (C) 2018 AACR.
URI
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-17-3262
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