1.JMJD1C forms condensate to facilitate a RUNX1-dependent gene expression program shared by multiple types of AML cells.
Qian CHEN ; Saisai WANG ; Juqing ZHANG ; Min XIE ; Bin LU ; Jie HE ; Zhuoran ZHEN ; Jing LI ; Jiajun ZHU ; Rong LI ; Pilong LI ; Haifeng WANG ; Christopher R VAKOC ; Robert G ROEDER ; Mo CHEN
Protein & Cell 2025;16(5):338-364
JMJD1C (Jumonji Domain Containing 1C), a member of the lysine demethylase 3 (KDM3) family, is universally required for the survival of several types of acute myeloid leukemia (AML) cells with different genetic mutations, representing a therapeutic opportunity with broad application. Yet how JMJD1C regulates the leukemic programs of various AML cells is largely unexplored. Here we show that JMJD1C interacts with the master hematopoietic transcription factor RUNX1, which thereby recruits JMJD1C to the genome to facilitate a RUNX1-driven transcriptional program that supports leukemic cell survival. The underlying mechanism hinges on the long N-terminal disordered region of JMJD1C, which harbors two inseparable abilities: condensate formation and direct interaction with RUNX1. This dual capability of JMJD1C may influence enhancer-promoter contacts crucial for the expression of key leukemic genes regulated by RUNX1. Our findings demonstrate a previously unappreciated role for the non-catalytic function of JMJD1C in transcriptional regulation, underlying a mechanism shared by different types of leukemias.
Core Binding Factor Alpha 2 Subunit/genetics*
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Humans
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Leukemia, Myeloid, Acute/pathology*
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Jumonji Domain-Containing Histone Demethylases/chemistry*
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Gene Expression Regulation, Leukemic
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Oxidoreductases, N-Demethylating/genetics*
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Cell Line, Tumor
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