Browse
Submit Data
Databases
API
Help

Dataset Information

26 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Loss of MBD2 attenuates MLL-AF9-driven leukemogenesis by suppressing the leukemic cell cycle via CDKN1C

ABSTRACT: Acute myeloid leukemia (AML) is a deadly cancer characterized by an expanded self-renewal capacity that is associated with the accumulation of immature myeloid cells. Emerging evidence shows that methyl-CpG-binding domain protein 2 (MBD2), a DNA methylation reader, often participates in the transcriptional silencing of hypermethylated genes in cancer cells. Nevertheless, the role of MBD2 in AML remains unclear. Herein, by using an MLL-AF9 murine model and a human AML cell line, we observed that loss of MBD2 could delay the initiation and progression of leukemia. MBD2 depletion significantly reduced the leukemia burden by decreasing the proportion of leukemic stem cells (LSCs) and inhibiting leukemia cell proliferation in serial transplantation experiments, thereby allowing leukemic blasts to transition to a more mature state reflecting normal myelopoiesis. Both gene expression analyses and bioinformatic studies revealed that MBD2 negatively modulated genes related to myeloid differentiation, and was necessary to sustain the MLL-AF9 oncogene-induced gene program. We further demonstrated that MBD2 could promote LSC cell cycle progression through epigenetic regulation of CDKN1C transcription probably by binding to its promoter region. Taken together, our data suggest that MBD2 promotes AML development and could be a therapeutic target for myeloid malignancies.

SUBMITTER: Zhou K

PROVIDER: S-EPMC8599466 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Loss of MBD2 Attenuates MLL-AF9-Driven Leukemogenesis By Reducing Leukemic Cell Cycling via CDKN1C

Project description:Emerging evidence supports that MBD2, a DNA methylation reader, often participated in the transcriptional silencing of hypermethylated genes in cancer cells. Nevertheless, the role of MBD2 in AML remains elusive. Herein, by using MLL-AF9 murine model and human AML cell line, we observed that loss of MBD2 could delay the initiation and propagation of leukemia through serial transplantation experiments. MBD2 depletion significantly reduced the leukemia burden by decreasing the frequency of leukemic stem cells (LSCs), coupled with inhibiting leukemia proliferation, thereby allowing leukemia blasts develop to a more mature state reflecting normal myelopoiesis. Both gene expression analyses and bioinformatic studies revealed that MBD2 negatively modulated the genes related to myeloid differentiation and was necessary to sustain MLL-AF9 oncogenic induced gene programs. We further demonstrated that MBD2 could promote LSC cell cycle progression through epigenetic regulation of CDKN1C transcription by binding to its promoter region. Taken together, our data suggested that MBD2 promotes AML development and could be a therapeutic target of myeloid malignancies.

2022-02-11 | GSE166610 | GEO

Loss of MBD2 Attenuates MLL-AF9-Driven Leukemogenesis By Reducing Leukemic Cell Cycling via CDKN1C

Project description:Loss of MBD2 Attenuates MLL-AF9-Driven Leukemogenesis By Reducing Leukemic Cell Cycling via CDKN1C

| PRJNA701410 | ENA

MLL-AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele.

Project description:Oncogenic fusion proteins are capable of initiating tumorigenesis, but the role of their wild-type counterparts in this process is poorly understood. The mixed lineage leukemia (MLL) gene undergoes chromosomal translocations, resulting in the formation of oncogenic MLL fusion proteins (MLL-FPs). Here, we show that menin recruits both wild-type MLL and oncogenic MLL-AF9 fusion protein to the loci of HOX genes to activate their transcription. Wild-type MLL not only catalyzes histone methylation at key target genes but also controls distinct MLL-AF9-induced histone methylation. Notably, the wild-type Mll allele is required for MLL-AF9-induced leukemogenesis and maintenance of MLL-AF9-transformed cells. These findings suggest an essential cooperation between an oncogene and its wild-type counterpart in MLL-AF9-induced leukemogenesis.

| S-EPMC2830208 | biostudies-literature

DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis.

Project description:Chromosomal translocations of the mixed lineage leukemia (MLL) gene are a common cause of acute leukemias. The oncogenic function of MLL fusion proteins is, in part, mediated through aberrant activation of Hoxa genes and Meis1, among others. Here we demonstrate using a tamoxifen-inducible Cre-mediated loss of function mouse model that DOT1L, an H3K79 methyltransferase, is required for both initiation and maintenance of MLL-AF9-induced leukemogenesis in vitro and in vivo. Through gene expression and chromatin immunoprecipitation analysis we demonstrate that mistargeting of DOT1L, subsequent H3K79 methylation, and up-regulation of Hoxa and Meis1 genes underlie the molecular mechanism of how DOT1L contributes to MLL-AF9-mediated leukemogenesis. Our study not only provides the first in vivo evidence for the function of DOT1L in leukemia, but also reveals the molecular mechanism for DOT1L in MLL-AF9 mediated leukemia. Thus, DOT1L may serve as a potential therapeutic target for the treatment of leukemia caused by MLL translocations.

| S-EPMC3128482 | biostudies-literature

CBX8, a polycomb group protein, is essential for MLL-AF9-induced leukemogenesis.

Project description:Chromosomal translocations involving the mixed lineage leukemia (MLL) gene lead to the development of acute leukemias. Constitutive HOX gene activation by MLL fusion proteins is required for MLL-mediated leukemogenesis; however, the underlying mechanisms remain elusive. Here, we show that chromobox homolog 8 (CBX8), a Polycomb Group protein that interacts with MLL-AF9 and TIP60, is required for MLL-AF9-induced transcriptional activation and leukemogenesis. Conversely, both CBX8 ablation and specific disruption of the CBX8 interaction by point mutations in MLL-AF9 abrogate HOX gene upregulation and abolish MLL-AF9 leukemic transformation. Surprisingly, Cbx8-deficient mice are viable and display no apparent hematopoietic defects. Together, our findings demonstrate that CBX8 plays an essential role in MLL-AF9 transcriptional regulation and leukemogenesis.

| S-EPMC3220883 | biostudies-literature

Smyd2 is a Myc-regulated gene critical for MLL-AF9 induced leukemogenesis.

Project description:The Smyd2 protein (Set- and Mynd domain containing protein 2) is a methyl-transferase that can modify both histones and cytoplasmic proteins. Smyd2 is over-expressed in several cancer types and was shown to be limiting for tumor development in the pancreas. However, genetic evidence for a role of Smyd2 in other cancers or in mouse development was missing to date. Using germ line-deleted mouse strains, we now show that Smyd2 and the related protein Smyd3 are dispensable for normal development. Ablation of Smyd2 did not affect hematopoiesis, but retarded the development of leukemia promoted by MLL-AF9, a fusion oncogene associated with acute myeloid leukemia (AML) in humans. Smyd2-deleted leukemic cells showed a competitive disadvantage relative to wild-type cells, either in vitro or in vivo. The Smyd2 gene was directly activated by the oncogenic transcription factor Myc in either MLL9-AF9-induced leukemias, Myc-induced lymphomas, or fibroblasts. However, unlike leukemias, the development of lymphomas was not dependent upon Smyd2. Our data indicate that Smyd2 has a critical role downstream of Myc in AML.

| S-EPMC5341809 | biostudies-literature

Histone Acetyltransferase Activity of MOF Is Required for <i>MLL-AF9</i> Leukemogenesis.

Project description:Chromatin-based mechanisms offer therapeutic targets in acute myeloid leukemia (AML) that are of great current interest. In this study, we conducted an RNAi-based screen to identify druggable chromatin regulator-based targets in leukemias marked by oncogenic rearrangements of the MLL gene. In this manner, we discovered the H4K16 histone acetyltransferase (HAT) MOF to be important for leukemia cell growth. Conditional deletion of Mof in a mouse model of MLL-AF9-driven leukemogenesis reduced tumor burden and prolonged host survival. RNA sequencing showed an expected downregulation of genes within DNA damage repair pathways that are controlled by MOF, as correlated with a significant increase in yH2AX nuclear foci in Mof-deficient MLL-AF9 tumor cells. In parallel, Mof loss also impaired global H4K16 acetylation in the tumor cell genome. Rescue experiments with catalytically inactive mutants of MOF showed that its enzymatic activity was required to maintain cancer pathogenicity. In support of the role of MOF in sustaining H4K16 acetylation, a small-molecule inhibitor of the HAT component MYST blocked the growth of both murine and human MLL-AF9 leukemia cell lines. Furthermore, Mof inactivation suppressed leukemia development in an NUP98-HOXA9-driven AML model. Taken together, our results establish that the HAT activity of MOF is required to sustain MLL-AF9 leukemia and may be important for multiple AML subtypes. Blocking this activity is sufficient to stimulate DNA damage, offering a rationale to pursue MOF inhibitors as a targeted approach to treat MLL-rearranged leukemias. Cancer Res; 77(7); 1753-62. ©2017 AACR.

| S-EPMC5501293 | biostudies-literature

Transient potential receptor melastatin-2 (Trpm2) does not influence murine MLL-AF9-driven AML leukemogenesis or in vitro response to chemotherapy.

Project description:Transient potential receptor melastatin-2 (TRPM2) is a nonselective cationic, Ca(2+)-permeable transmembrane pore that is preferentially expressed in cells of the myeloid lineage and modulates signaling pathways converging into NF-kB. This is of potential interest for acute myeloid leukemia (AML) therapy, as NF-?B signaling is emerging as a key pathway, mediating drug resistance and leukemia-initiating cell survival in AML. Inhibition of NF-?B signaling has been found to be synergistic with chemotherapy. TRPM2 is overexpressed in AML compared with normal bone marrow, with the highest levels in the FAB M3-6 subtypes. To determine the effect of TRPM2 depletions in a defined genetic model, we established MLL-AF9-driven AML on a Trpm2(-/-) genetic background. Trpm2(-/-) MLL-AF9 leukemias displayed reduced NF-?B phosphorylation as well as nuclear translocation. In vivo, primary and secondary recipients of Trpm2(-/-) MLL-AF9 leukemias exhibit increased latency compared with recipients of wild-type leukemia cells. However, the difference in latency was small and was lost in tertiary transplants. The effect of loss of Trpm2 in a BCR-ABL/NUP98-HOXA9 fusion model was even smaller. Given reports that loss or inhibition of TRPM2 enhanced killing by DNA-damaging agents in neuroblastoma, breast cancer, and prostate cancer cell lines, we exposed Trpm2(-/-) and Trpm2(wt) primary MLL-AF9 leukemias to doxorubicin, cytarabine, and etoposide, but found no difference in IC50 values. The in vitro response to decitabine was also unaffected. In summary, Trpm2 does not seem to play a major role in myeloid leukemogenesis. Additionally, loss of Trpm2 does not augment the cytotoxicity of standard AML chemotherapeutic agents.

| S-EPMC4914470 | biostudies-literature

Differential roles of BAF and PBAF subunits, Arid1b and Arid2, in MLL-AF9 leukemogenesis.

Project description:The Switch/Sugar Non-Fermenting (SWI/SNF) nucleosome remodeling complexes play important roles in normal development and in the development of various cancers. Core subunits of the SWI/SNF complexes have been shown to have oncogenic roles in acute myeloid leukemia. However, the roles of the unique targeting subunits, including that of Arid2 and Arid1b, in AML leukemogenesis are not well understood. Here, we used conditional knockout mouse models to elucidate their role in MLL-AF9 leukemogenesis. We uncovered that Arid2 has dual roles; enhancing leukemogenesis when deleted during leukemia initiation and yet is required during leukemia maintenance. Whereas, deleting Arid1b in either phase promotes leukemogenesis. Our integrated analyses of transcriptomics and genomic binding data showed that, globally, Arid2 and Arid1b regulate largely distinct sets of genes at different disease stages, respectively, and in comparison, to each other. Amongst the most highly dysregulated transcription factors upon their loss, Arid2 and Arid1b converged on the regulation of Etv4/Etv5, albeit in an opposing manner while also regulating distinct TFs including Gata2,Tcf4, Six4, Irf4 and Hmgn3. Our data demonstrate the differential roles of SWI/SNF subunits in AML leukemogenesis and emphasize that cellular context and disease stage are key in determining their functions during this process.

| S-EPMC10095935 | biostudies-literature

Hematopoietic Stem Cell (HSC)-Independent Progenitors Are Susceptible to Mll-Af9-Induced Leukemic Transformation.

Project description:Infant acute myeloid leukemia (AML) is a heterogeneous disease, genetically distinct from its adult counterpart. Chromosomal translocations involving the KMT2A gene (MLL) are especially common in affected infants of less than 1 year of age, and are associated with a dismal prognosis. While these rearrangements are likely to arise in utero, the cell of origin has not been conclusively identified. This knowledge could lead to a better understanding of the biology of the disease and support the identification of new therapeutic vulnerabilities. Over the last few years, important progress in understanding the dynamics of fetal hematopoiesis has been made. Several reports have highlighted how hematopoietic stem cells (HSC) provide little contribution to fetal hematopoiesis, which is instead largely sustained by HSC-independent progenitors. Here, we used conditional Cre-Lox transgenic mouse models to engineer the Mll-Af9 translocation in defined subsets of embryonic hematopoietic progenitors. We show that embryonic hematopoiesis is generally permissive for Mll-Af9-induced leukemic transformation. Surprisingly, the selective introduction of Mll-Af9 in HSC-independent progenitors generated a transplantable myeloid leukemia, whereas it did not when introduced in embryonic HSC-derived cells. Ex vivo engineering of the Mll-Af9 rearrangement in HSC-independent progenitors using a CRISPR/Cas9-based approach resulted in the activation of an aberrant myeloid-biased self-renewal program. Overall, our results demonstrate that HSC-independent hematopoietic progenitors represent a permissive environment for Mll-Af9-induced leukemic transformation, and can likely act as cells of origin of infant AML.

| S-EPMC10377085 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data