T-lineage acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that accounts for 10%–15% of pediatric and 25% of adult ALL cases. Although the prognosis of T-ALL has improved over time, the outcome of T-ALL patients with primary resistant or relapsed leukemia remains poor. Therefore, further progress in the treatment of T-ALL requires a better understanding of its biology and the development of more effective precision oncologic therapies. The proto-oncogene MYB is highly expressed in diverse hematologic malignancies, including T-ALLs with genomic aberrations that further potentiate its expression and activity. Previous studies have associated MYB with a malignant role in the pathogenesis of several cancers. However, its role in the induction and maintenance of T-ALL remains relatively poorly understood. In this study, we found that an increased copy number of MYB is associated with higher MYB expression levels, and might be associated with inferior event-free survival of pediatric T-ALL patients. Using our previously described conditional Myb overexpression mice, we generated two distinct MYB-driven T-ALL mouse models. We demonstrated that the overexpression of Myb synergizes with Pten deletion but not with the overexpression of Lmo2 to accelerate the development of T-cell lymphoblastic leukemias. We also showed that MYB is a dependency factor in T-ALL since RNA interference of Myb blocked cell cycle progression and induced apoptosis in both human and murine T-ALL cell lines. Finally, we provide preclinical evidence that targeting the transcriptional activity of MYB can be a useful therapeutic strategy for the treatment of T-ALL.

Myb overexpression synergizes with the loss of Pten and is a dependency factor and therapeutic target in T-cell lymphoblastic leukemia / Almeida, A.; T'Sas, S.; Pagliaro, L.; Fijalkowski, I.; Sleeckx, W.; Van Steenberge, H.; Zamponi, R.; Lintermans, B.; Van Loocke, W.; Palhais, B.; Reekmans, A.; Bardelli, V.; Demoen, L.; Reunes, L.; Deforce, D.; Van Nieuwerburgh, F.; Kentsis, A.; Ntziachristos, P.; Van Roy, N.; De Moerloose, B.; Mecucci, C.; La Starza, R.; Roti, G.; Goossens, S.; Van Vlierberghe, P.; Pieters, T.. - In: HEMASPHERE. - ISSN 2572-9241. - 8:3(2024). [10.1002/hem3.51]

Myb overexpression synergizes with the loss of Pten and is a dependency factor and therapeutic target in T-cell lymphoblastic leukemia

Pagliaro L.;Zamponi R.;Mecucci C.;Roti G.;
2024-01-01

Abstract

T-lineage acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that accounts for 10%–15% of pediatric and 25% of adult ALL cases. Although the prognosis of T-ALL has improved over time, the outcome of T-ALL patients with primary resistant or relapsed leukemia remains poor. Therefore, further progress in the treatment of T-ALL requires a better understanding of its biology and the development of more effective precision oncologic therapies. The proto-oncogene MYB is highly expressed in diverse hematologic malignancies, including T-ALLs with genomic aberrations that further potentiate its expression and activity. Previous studies have associated MYB with a malignant role in the pathogenesis of several cancers. However, its role in the induction and maintenance of T-ALL remains relatively poorly understood. In this study, we found that an increased copy number of MYB is associated with higher MYB expression levels, and might be associated with inferior event-free survival of pediatric T-ALL patients. Using our previously described conditional Myb overexpression mice, we generated two distinct MYB-driven T-ALL mouse models. We demonstrated that the overexpression of Myb synergizes with Pten deletion but not with the overexpression of Lmo2 to accelerate the development of T-cell lymphoblastic leukemias. We also showed that MYB is a dependency factor in T-ALL since RNA interference of Myb blocked cell cycle progression and induced apoptosis in both human and murine T-ALL cell lines. Finally, we provide preclinical evidence that targeting the transcriptional activity of MYB can be a useful therapeutic strategy for the treatment of T-ALL.
2024
Myb overexpression synergizes with the loss of Pten and is a dependency factor and therapeutic target in T-cell lymphoblastic leukemia / Almeida, A.; T'Sas, S.; Pagliaro, L.; Fijalkowski, I.; Sleeckx, W.; Van Steenberge, H.; Zamponi, R.; Lintermans, B.; Van Loocke, W.; Palhais, B.; Reekmans, A.; Bardelli, V.; Demoen, L.; Reunes, L.; Deforce, D.; Van Nieuwerburgh, F.; Kentsis, A.; Ntziachristos, P.; Van Roy, N.; De Moerloose, B.; Mecucci, C.; La Starza, R.; Roti, G.; Goossens, S.; Van Vlierberghe, P.; Pieters, T.. - In: HEMASPHERE. - ISSN 2572-9241. - 8:3(2024). [10.1002/hem3.51]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/3003554
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