2026-09-16T03:58:00Zhttps://gredos.usal.es/oai/request

oai:gredos.usal.es:10366/1553612025-04-30T19:28:40Zcom_10366_3974com_10366_3947com_10366_3946com_10366_3823col_10366_3975

Martín Lorenzo, Alberto Auer, Franziska Chan, Lai N. García Ramírez, Idoia González-Herrero, Inés Rodríguez Hernández, Guillermo Bartenhagen, Christoph Dugas, Martin Gombert, Michael Ginzel, Sebastian Blanco Muñez, Óscar Javier Orfao de Matos Correia e Vale, José Alberto Alonso López, Diego Rivas Sanz, Javier de las García Cenador, María Begoña García Criado, Francisco Javier Müschen, Markus Sánchez García, Isidro Borkhardt, Arndt Vicente Dueñas, Carolina Hauer, Julia 2018 [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. http://hdl.handle.net/10366/155361 eng American Association for Cancer Research 3201.01 Oncología Loss of Pax5 exploits sca1-BCR-ABLp190 susceptibility to confer the metabolic shift essential for pB-ALL info:eu-repo/semantics/article TEXT Gredos. Repositorio Documental de la Universidad de Salamanca Hispana