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

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

JCI insight (2022-05-11)
Kirsten Canté-Barrett, Mariska T Meijer, Valentina Cordo', Rico Hagelaar, Wentao Yang, Jiyang Yu, Willem K Smits, Marloes E Nulle, Joris P Jansen, Rob Pieters, Jun J Yang, Jody J Haigh, Steven Goossens, Jules Pp Meijerink
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.

MATERIALS
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Brand
Product Description

Sigma-Aldrich
TAT-CRE Recombinase, TAT-CRE Recombinase is a recombinant cell-permeant fusion cre-recombinase protein consisting of TAT sequence, a nuclear localization sequence (NLS) and it is known to catalyze the site specific recombination event between two loxP DNA sites.
Sigma-Aldrich
Dasatinib
Sigma-Aldrich
Anti-SIK3 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution