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Critical role of Jumonji domain of JMJD1C in MLL-rearranged leukemia. Blood Adv 2019 05 14;3(9):1499-1511



Pubmed ID


Pubmed Central ID




Scopus ID

2-s2.0-85068626845   3 Citations


JMJD1C, a member of the lysine demethylase 3 family, is aberrantly expressed in mixed lineage leukemia (MLL) gene-rearranged (MLLr) leukemias. We have shown previously that JMJD1C is required for self-renewal of acute myeloid leukemia (AML) leukemia stem cells (LSCs) but not normal hematopoietic stem cells. However, the domains within JMJD1C that promote LSC self-renewal are unknown. Here, we used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) negative-selection screening and identified a requirement for the catalytic Jumonji (JmjC) domain and zinc finger domain for leukemia cell survival in vitro and in vivo. In addition, we found that histone H3 lysine 36 methylation (H3K36me) is a marker for JMJD1C activity at gene loci. Moreover, we performed single cell transcriptome analysis of mouse leukemia cells harboring a single guide RNA (sgRNA) against the JmjC domain and identified increased activation of RAS/MAPK and the JAK-STAT pathway in cells harboring the JmjC sgRNA. We discovered that upregulation of interleukin 3 (IL-3) receptor genes mediates increased activation of IL-3 signaling upon JMJD1C loss or mutation. Along these lines, we observed resistance to JMJD1C loss in MLLr AML bearing activating RAS mutations, suggesting that RAS pathway activation confers resistance to JMJD1C loss. Overall, we discovered the functional importance of the JMJD1C JmjC domain in AML leukemogenesis and a novel interplay between JMJD1C and the IL-3 signaling pathway as a potential resistance mechanism to targeting JMJD1C catalytic activity.

Author List

Izaguirre-Carbonell J, Christiansen L, Burns R, Schmitz J, Li C, Mokry RL, Bluemn T, Zheng Y, Shen J, Carlson KS, Rao S, Wang D, Zhu N


Karen-Sue B. Carlson MD, PhD Assistant Professor in the Medicine department at Medical College of Wisconsin
Sridhar Rao MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Demin Wang PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

CRISPR-Cas Systems
Cell Line, Tumor
Gene Editing
Histone-Lysine N-Methyltransferase
Jumonji Domain-Containing Histone Demethylases
Leukemia, Myeloid, Acute
Mice, Inbred C57BL
Myeloid-Lymphoid Leukemia Protein
Oxidoreductases, N-Demethylating
Protein Domains
RNA, Guide
Signal Transduction
Transplantation, Heterologous
Zinc Fingers
jenkins-FCD Prod-469 c3fc8ab87196149f9b23743c01b947d47e7319e5