TY - JOUR
T1 - MEF2C opposes Notch in lymphoid lineage decision and drives leukemia in the thymus
AU - Canté-Barrett, Kirsten
AU - Meijer, Mariska T.
AU - Cordo, Valentina
AU - Hagelaar, Rico
AU - Yang, Wentao
AU - Yu, Jiyang
AU - Smits, Willem K.
AU - Nulle, Marloes E.
AU - Jansen, Joris P.
AU - Pieters, Rob
AU - Yang, Jun J.
AU - Haigh, Jody J.
AU - Goossens, Steven
AU - Meijerink, Jules P.P.
N1 - Publisher Copyright:
Copyright: © 2022, Canté-Barrett et al.
PY - 2022/7/8
Y1 - 2022/7/8
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85133930244
U2 - 10.1172/jci.insight.150363
DO - 10.1172/jci.insight.150363
M3 - Article
C2 - 35536646
AN - SCOPUS:85133930244
SN - 2379-3708
VL - 7
JO - JCI Insight
JF - JCI Insight
IS - 13
M1 - e150363
ER -