JMJD1C is required for the survival of acute myeloid leukemia by functioning as a coactivator for key transcription factors

Abstract

RUNX1-RUNX1T1 (formerly AML1-ETO), a transcription factor generated by the t(8;21) translocation in acute myeloid leukemia (AML), dictates a leukemic program by increasing self-renewal and inhibiting differentiation. Here we demonstrate that the histone demethylase JMJD1C functions as a coactivator for RUNX1-RUNX1T1 and is required for its transcriptional program. JMJD1C is directly recruited by RUNX1-RUNX1T1 to its target genes and regulates their expression by maintaining low H3K9 dimethyl (H3K9me2) levels. Analyses in JMJD1C knockout mice also establish a JMJD1C requirement for RUNX1-RUNX1T1's ability to increase proliferation. We also show a critical role for JMJD1C in the survival of multiple human AML cell lines, suggesting that it is required for leukemic programs in different AML cell types through its association with key transcription factors.[Keywords: AML1-ETO; acute myeloid leukemia; HEB; histone demethylase; LYL1; transcription regulation] Supplemental material is available for this article. Hematopoiesis is controlled by the differential expression of key transcription factors that act cooperatively to maintain a well-orchestrated balance of hematopoietic stem cell (HSC) self-renewal and differentiation (Wilson et al. 2010). These functions of transcription factors are frequently dysregulated in leukemia by chromosomal translocations, mutations, or aberrant expression and lead to abnormal self-renewal (Look 1997). RUNX1-RUNX1T1 (commonly referred to as acute myeloid leukemia 1 [AML1]-ETO and referred to here as AE), generated by the t(8; 21) translocation, occurs in ∼15% of AML cases (Look 1997;Kaspers and Zwaan 2007) and acts to enhance self-renewal and inhibit myeloid differentiation.

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

“…52 In human myeloid leukemia cells, JMJD1C functions as a coactivator for the leukemogenic transcriptional complex RUNX1-RUNX1T1 to increase AML cell proliferation and survival. 53 An intergenic variant rs2836878 located between ETS2 and PSMG1 showed evidence of multi-lineage association with lower total WBC count across all myeloid cell types and to a lesser extent with lower platelet count and higher hemoglobin (Table S12); rs2836878 is a wholeblood eQTL for ETS2 (Table S13). ETS2 is another protooncogene that encodes for a transcription factor involved in stem cell development, cell senescence, and death, whereas the product of PSMG1 is involved in maturation of proteasomes.…”

New insights into transcriptional and leukemogenic mechanisms of AML1-ETO and E2A fusion proteins

“…Adding to the list of AML1-ETO co-activators, JMJD1C, a histone H3K9 demethylase, was shown to bind to (Fig. 2) and mediate AML1-ETO-dependent activation of target genes (Chen et al, 2015). JMJD1C may play a broader role in leukemogenesis given its requirement for survival of multiple human AML cell lines (Chen et al, 2015).…”

“…Some of the transcription factors may interact with AML1-ETO indirectly through the proximal binding sites on target DNA. Proteins bound to the ETO portion of the fusion protein include: Atrophin-1 (Wood et al, 2000), Dnmt1 (Liu et al, 2005), SHARP (Salat et al, 2008), JMJD1c (Chen et al, 2015), PLZF (Melnick et al, 2000), Bcl6 (Chevallier et al, 2004), HEB/E2A/LYL1/LMO2/Ldb1(Sun et al, 2013), Gfi1 (McGhee et al, 2003), corepressors NCoR/SMRT/HDAC3, mSin3A/HDAC1/2 (Gelmetti et al, 1998; Lutterbach et al, 1998b; Wang et al, 1998; Amann et al, 2001; Hildebrand et al, 2001; Zhang et al, 2001), p300 (Wang et al, 2011a), HSP90 (Komori et al, 1999), ETO-2/MTGR1 (Kitabayashi et al, 1998; Liu et al, 2006), PKA(RIIα) (Fukuyama et al, 2001), and SON (Ahn et al, 2008). PRMT1 binds to AML1-ETO9a fragment (Shia et al, 2012).…”

Lysine-specific histone demethylases in normal and malignant hematopoiesis

“…Notably, although JMJD1C is important for the maintenance of the malignant phenotype, it is dispensable for leukemia initiation (41). Although originally reported to be an H3K9me2/me1 demethylase leading to transcriptional activation, subsequent studies failed to detect demethylase activity for JMJD1C (40-42). Thus, the question whether the role of JMJD1C in leukemia maintenance relies on its demethylation activity remains open.…”

“…JMJD1C is another JmjC domain protein discovered as putative oncogene in shRNA screens in MLL-AF9, HOXA9, and AML1-ETO driven AML (40-42). Depletion of JMJD1C decreased the frequency of leukemia initiating cells by inducing their differentiation and impaired the growth and establishment of leukemia in serial transplantation experiments.…”