Unknown

Dataset Information

0

MEF2C opposes Notch in lymphoid lineage decision and drives leukemia in the thymus.


ABSTRACT: Rearrangements that drive ectopic MEF2C expression have recurrently been found in patients with human early thymocyte progenitor acute lymphoblastic leukemia (ETP-ALL). Here, we show high levels of MEF2C expression in patients with ETP-ALL. Using both in vivo and in vitro models of ETP-ALL, we demonstrate that elevated MEF2C expression blocks NOTCH-induced T cell differentiation while promoting a B-lineage program. MEF2C activates a B cell transcriptional program in addition to RUNX1, GATA3, and LMO2; upregulates the IL-7R; and boosts cell survival by upregulation of BCL2. MEF2C and the Notch pathway, therefore, demarcate opposite regulators of B- or T-lineage choices, respectively. Enforced MEF2C expression in mouse or human progenitor cells effectively blocks early T cell differentiation and promotes the development of biphenotypic lymphoid tumors that coexpress CD3 and CD19, resembling human mixed phenotype acute leukemia. Salt-inducible kinase (SIK) inhibitors impair MEF2C activity and alleviate the T cell developmental block. Importantly, this sensitizes cells to prednisolone treatment. Therefore, SIK-inhibiting compounds such as dasatinib are potentially valuable additions to standard chemotherapy for human ETP-ALL.

SUBMITTER: Cante-Barrett K 

PROVIDER: S-EPMC9310523 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

2022-05-14 | GSE160409 | GEO
2022-05-14 | GSE159506 | GEO
2022-05-14 | GSE160407 | GEO
| PRJNA673173 | ENA
| PRJNA670296 | ENA
| PRJNA673305 | ENA
| S-EPMC2978506 | biostudies-literature
| S-EPMC9329340 | biostudies-literature
| S-EPMC5159664 | biostudies-literature
| S-EPMC4987520 | biostudies-literature