Similar Datasets
Project description: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.
| S-EPMC6517669 | biostudies-literature
Project description:Critical Role of Jumonji Domain of JMJD1C in MLL-rearranged leukemia
| PRJNA532423 | ENA
Project description:We performed single-cell sequencing on mouse MLL-AF9-cas9 leukemia cells 7 days after transduction with sgRNA against Renilla or JMJD1C JmjC domain. We revealed heterogeneity within each population.
2019-04-12 | GSE129662 | GEO
Project description:The ten-eleven translocation 1 (TET1) gene is the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine to 5-hydroxymethylcytosine. Although TET1 was first identified as a fusion partner of the mixed lineage leukemia (MLL) gene in acute myeloid leukemia carrying t(10,11), its definitive role in leukemia is unclear. In contrast to the frequent down-regulation (or loss-of-function mutations) and critical tumor-suppressor roles of the three TET genes observed in various types of cancers, here we show that TET1 is a direct target of MLL-fusion proteins and is significantly up-regulated in MLL-rearranged leukemia, leading to a global increase of 5-hydroxymethylcytosine level. Furthermore, our both in vitro and in vivo functional studies demonstrate that Tet1 plays an indispensable oncogenic role in the development of MLL-rearranged leukemia, through coordination with MLL-fusion proteins in regulating their critical cotargets, including homeobox A9 (Hoxa9)/myeloid ecotropic viral integration 1 (Meis1)/pre-B-cell leukemia homeobox 3 (Pbx3) genes. Collectively, our data delineate an MLL-fusion/Tet1/Hoxa9/Meis1/Pbx3 signaling axis in MLL-rearranged leukemia and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease.
| S-EPMC3718141 | biostudies-literature
Project description:Chromosomal translocations of the mixed-lineage leukemia (MLL) gene with various partner genes result in aggressive leukemia with dismal outcomes. Despite similar expression at the mRNA level from the wild-type and chimeric MLL alleles, the chimeric protein is more stable. We report that UBE2O functions in regulating the stability of wild-type MLL in response to interleukin-1 signaling. Targeting wild-type MLL degradation impedes MLL leukemia cell proliferation, and it downregulates a specific group of target genes of the MLL chimeras and their oncogenic cofactor, the super elongation complex. Pharmacologically inhibiting this pathway substantially delays progression, and it improves survival of murine leukemia through stabilizing wild-type MLL protein, which displaces the MLL chimera from some of its target genes and, therefore, relieves the cellular oncogenic addiction to MLL chimeras. Stabilization of MLL provides us with a paradigm in the development of therapies for aggressive MLL leukemia and perhaps for other cancers caused by translocations.
| S-EPMC5351781 | biostudies-literature
Project description:Single-cell sequencing of JMJD1C Jumonji domain mutated MLL-AF9 Leukemia cells
| PRJNA532410 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-09-22 | GSE213990 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-06-29 | E-GEOD-68463 | biostudies-arrayexpress
Project description:The MLL1 histone methyltransferase gene undergoes many distinct chromosomal rearrangements to yield poor-prognosis leukemia. The remaining wild-type allele is most commonly, but not always, retained. To what extent the wild-type allele contributes to leukemogenesis is unclear. Here we show, using rigorous, independent animal models, that endogenous MLL1 is dispensable for MLL-rearranged leukemia. Potential redundancy was addressed by co-deleting the closest paralog, Mll2. Surprisingly, Mll2 deletion alone had a significant impact on survival of MLL-AF9-transformed cells, and additional Mll1 loss further reduced viability and proliferation. We show that MLL1/MLL2 collaboration is not through redundancy, but regulation of distinct pathways. These findings highlight the relevance of MLL2 as a drug target in MLL-rearranged leukemia and suggest its broader significance in AML.
| S-EPMC5598468 | biostudies-literature
Project description:Self-renewal is a hallmark of both hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs); therefore, the identification of mechanisms that are required for LSC, but not HSC, function could provide therapeutic opportunities that are more effective and less toxic than current treatments. Here, we employed an in vivo shRNA screen and identified jumonji domain-containing protein JMJD1C as an important driver of MLL-AF9 leukemia. Using a conditional mouse model, we showed that loss of JMJD1C substantially decreased LSC frequency and caused differentiation of MLL-AF9- and homeobox A9-driven (HOXA9-driven) leukemias. We determined that JMJD1C directly interacts with HOXA9 and modulates a HOXA9-controlled gene-expression program. In contrast, loss of JMJD1C led to only minor defects in blood homeostasis and modest effects on HSC self-renewal. Together, these data establish JMJD1C as an important mediator of MLL-AF9- and HOXA9-driven LSC function that is largely dispensable for HSC function.
| S-EPMC4767347 | biostudies-literature