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Critical role of Jumonji domain of JMJD1C in MLL-rearranged leukemia

Jesus Izaguirre-Carbonell, Luke Christiansen, Robert Burns, Jesse Schmitz, Chenxuan Li, Rebekah L. Mokry, Theresa Bluemn, Yongwei Zheng, Jian Shen, Karen-Sue Carlson, Sridhar Rao, Demin Wang and Nan Zhu

Key Points

  • CRISPR/Cas9 screen identified JMJD1C Jumonji domain as critical for MLLr leukemogenesis. H3K36me is a marker for JMJD1C activity.

  • JMJD1C loss leads to increased IL-3 signaling. This effect is blunted in leukemia cells with activating RAS mutations.

Abstract

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.

  • Submitted September 13, 2018.
  • Accepted March 31, 2019.
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