Journal
JCI INSIGHT
Volume 7, Issue 13, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.150363
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Funding
- Dutch Kinderen Kanker Vrij foundation [KiKa-295, KiKa-219]
- Dutch Cancer Society grant [KWF-10355]
- University Medical Center of Utrecht
- Hubrecht Laboratory
- University of Utrecht
- Netherlands X-omics Initiative [184.034.019]
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This study found that elevated MEF2C expression is associated with ETP-ALL and blocks T cell differentiation while promoting the B-lineage program. MEF2C activates a B cell transcriptional program and enhances cell survival. Inhibiting SIK can alleviate the T cell developmental block and enhance sensitivity to prednisolone treatment.
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.
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