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

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JMJD1C forms condensate to facilitate a RUNX1-dependent gene expression program shared by multiple types of AML cells.

Author: Qian CHEN ¹ ; Saisai WANG ¹ ; Juqing ZHANG ² ; Min XIE ³ ; Bin LU ⁴ ; Jie HE ⁵ ; Zhuoran ZHEN ⁶ ; Jing LI ⁷ ; Jiajun ZHU ⁶ ; Rong LI ⁵ ; Pilong LI ⁸ ; Haifeng WANG ² ; Christopher R VAKOC ⁴ ; Robert G ROEDER ⁹ ; Mo CHEN ¹
Author Information

1. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China.
2. School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Center for Synthetic and Systems Biology, Tsinghua University, Beijing 100084, China.
3. School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China.
4. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, United States.
5. Nuclear Radiation Injury Protection and Treatment Department, Navy Medical Center of People Liberation Army (PLA), Second Military Medical University (Naval Medical University), Shanghai 200052, China.
6. State Key Laboratory of Molecular Oncology, Tsinghua-Peking Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China.
7. Department of Precision Medicine, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai 200433, China.
8. State Key Laboratory of Membrane Biology, Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University-Peking University Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China.
9. Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, United States.
Publication Type:Journal Article
Keywords: JMJD1C; RUNX1; acute myeloid leukemia; enhancer-promoter interaction; enzymatic activity independent function; phase separation
MeSH: Core Binding Factor Alpha 2 Subunit/genetics*; Humans; Leukemia, Myeloid, Acute/pathology*; Jumonji Domain-Containing Histone Demethylases/chemistry*; Gene Expression Regulation, Leukemic; Oxidoreductases, N-Demethylating/genetics*; Cell Line, Tumor
From: Protein & Cell 2025;16(5):338-364
CountryChina
Language:English
Abstract: 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.