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Progenitor like cell type of an MLL-EDC4 fusion in acute myeloid leukemia

ABSTRACT: Transcriptome analysis by single cell sequencing provides valuable information on intratumor heterogeneity and developmental stages of acute myeloid leukemia (AML) as well as interactions of tumor cells with the microenvironment. However, it has been hardly applied to the subgroup of cases with translocations of the mixed lineage leukemia (MLL) gene for which the enhancer of mRNA decapping 4 (EDC4) gene was recently identified as a novel fusion partner (MLL-EDC4). Here, we compared different MLL translocation by single cell RNA sequencing of cells derived from peripheral blood. The AML MLL-EDC4 patient almost exclusively showed a transcriptional profile of hematopoietic progenitor cells while leukemic cells while the MLLT3-MLL and MLL-ELL fusions exhibited a more differentiated phenotype. The MLL-EDC4 progenitor state was characterized by the upregulation of key transcriptional regulators in AML (RUNX1, SOX4, HOPX), target genes of MYC and interferon signaling as well as other genes known to play a critical role in hematopoiesis or leukemic stem cell activation (CDK6, FLT3, NPM1). In addition, we detected an enrichment of a normal and putatively immunosuppressive monocyte population in the patient with MLL-EDC4. Thus, the MLL-EDC4 translocation was associated with unique transcriptional and microenvironmental features.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214240 | GEO | 2022/09/29

REPOSITORIES: GEO

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Enhancer-activated RET confers protection against oxidative stress to KMT2A-rearranged acute myeloid leukemia.

Project description:KMT2A-MLLT3, a fusion protein formed by the t(9;11) translocation in acute myeloid leukemia, is an epigenetic transcription factor that is known to regulate a unique leukemic gene expression profile. We show that rearranged during transfection (RET) proto-oncogene is highly overexpressed in the KMT2A-MLLT3 subgroup. In addition to biochemical studies, the RNA-seq and ATAC seq analyses have been performed in KMT2A-MLLT3 positive MOLM-13 AML cell line, compared to the umbilical cord blood-driven CD34+ hematopoietic stem progenitor cells.

2024-03-04 | GSE241867 | GEO

RNAi-mediated silencing of MLL-AF9 reveals leukemia-associated downstream targets and processes

Project description:The translocation t(9;11)(p22;q23) leading to the leukemogenic fusion gene MLL-AF9 is a frequent translocation in infant acute myeloid leukemia (AML). This study aimed to identify genes and molecular processes downstream of MLL-AF9 (alias MLL-MLLT3) which could assist to develop new targeted therapies for such leukemia with unfavorable prognosis. In the AML cell line THP1 which harbors this t(9;11) translocation, endogenous MLL-AF9 was silenced via siRNA while ensuring specificity of the knockdown and its efficiency on functional protein level. The differential gene expression profile was validated for leukemia-association by gene set enrichment analysis of published gene sets from patient studies and MLL-AF9 overexpression studies and revealed 425 differentially expressed genes. Gene ontology analysis was consistent with a more differentiated state of MLL-AF9 depleted cells, with involvement of a wide range of downstream transcriptional regulators and with defined functional processes such as ribosomal biogenesis, chaperone binding, calcium homeostasis and estrogen response. Besides potential new therapeutic targets, the described transcription profile shaped by MLL-AF9 provides an information source into the molecular processes altered in MLL aberrant leukemia. 4 samples were analyzed, each corresponding to a pool of five independent replicate experiments. MLL-AF9 knockdown treatments are represented by 2 pooled samples employing two distinct siRNAs, each targeting MLL-AF9 breakpoint of THP1 cells. Control treatments are represented by 2 pooled samples employing two distinct non-targeting control siRNAs. siRNA-3 = siRNA-A in publication siRNA-4 = siRNA-B in publication

2014-02-13 | E-GEOD-36592 | biostudies-arrayexpress

RNAi-mediated silencing of MLL-AF9 reveals leukemia-associated downstream targets and processes

2014-02-13 | GSE36592 | GEO

RNA-seq profiling of murine Tet-off MLL-AF9; NRAS acute myeloid leukemia at different timepoints upon doxycycline-induced MLL-AF9 down-regulation.

Project description:Using an acute myeloid leukemia (AML) mouse model driven by tet-regulated MLL-AF9 (fusion between the gene MLL1 (KMT2A/MLL) and MLLT3 (AF9)) co-expressed with oncogenic NRASG12D (Tet-off MLL-AF9), we investigated the effect of modulating the expression of the MLL-AF9 fusion oncogene on the transcriptome and proteome of established murine AML. Treatment in vitro or in vivo of these Tet-off MLL-AF9 AMLs with doxycycline (DOX) results in the efficient down-regulation of the expression of the driver oncogene MLL-AF9. RNA sequencing analysis was performed on primary Tet-Off MLL-AF9 AML cells obtained from the spleen of leukemic animals and cultured in vitro for either 2 or 4 days in the presence of doxycycline (1μg/ml) (DOX= down-regulation of MLL-AF9) or left untreated (UT).

2021-12-31 | GSE108326 | GEO

Bortezomib suppresses self-renewal and leukemogenesis of leukemia stem cell by NF-ĸB-dependent inhibition of cyclin dependent kinase 6 in MLL-rearranged myeloid leukemia

Project description:Acute myeloid leukemia (AML) with chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukemia (MLL) is an aggressive subtype with low overall survival. MLL rearrangements rapidly transform hematological stem and progenitor cell (HSPC) to leukemia stem cell (LSC). Bortezomib (Velcade) is used widely in hematological malignancies. However, it is still unknown whether bortezomib possesses anti-self-renewal and anti-leukemogenesis of LSC in AML with MLL rearrangements. Here, we found that bortezomib inhibited cell proliferation, induced apoptosis, and decreased colony formation in leukemic cell lines, primary AML blasts, and MLL-AF9-transformed murine leukemic blasts. Besides, bortezomib reduced the frequency and function of LSC, inhibited the progression, and prolonged

2022-08-10 | GSE157702 | GEO

Hematopoietic cell differentiation is required for initiation of acute myeloid leukemia [Microarray expression]

Project description:Leukemia initiating cells (LICs) of acute myeloid leukemia (AML) may arise from self-renewing hematopoietic stem cells (HSCs) and from committed progenitors. However, it remains unclear how leukemia-associated oncogenes instruct LIC formation from cells of different origins and if differentiation along the normal hematopoietic hierarchy is involved. Here, using murine models with the driver mutations MLL-AF9 or MOZ-TIF2, we found that regardless of the transformed cell types, myelomonocytic differentiation to the granulocyte macrophage progenitor (GMP) stage is critical for LIC generation. Blocking myeloid differentiation through disrupting the lineage-restricted transcription factor C/EBPa eliminates GMPs, blocks normal granulopoiesis, and prevents AML development. In contrast, restoring myeloid differentiation through inflammatory cytokines “rescues” AML transformation. Our findings identify myeloid differentiation as a critical step in LIC formation and AML development, thus guiding new therapeutic approaches. Primary KSL, CMP, and GMP cells from wildtype controls and C/Ebpa knockouts were used for RNA extraction and hybridization on Affymetrix microarrays. We also compared the microarray samples of leukemic granulocyte macrophage progenitor compartments (L-GMPs) from MLL-AF9 transformed control or cytokine rescued C/EBPa KO leukemic mouse bone marrow and their secondary recipients with those non-Leukemia KSLs and CMPs from MLL-AF9 transduecd KO recipients with no leukemia development.

2015-08-04 | E-GEOD-71687 | biostudies-arrayexpress

Hematopoietic cell differentiation is required for initiation of acute myeloid leukemia

2014-09-17 | E-GEOD-61468 | biostudies-arrayexpress

FLT3-N676K drives acute myeloid leukemia in a xenograft model of KMT2A-MLLT3 leukemogenesis

Project description:Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements. Herein, we show that co-expression of FLT3-N676K and KMT2A-MLLT3 in human CD34+ cord blood cells primarily cause acute myeloid leukemia (AML) and rarely acute lymphoblastic leukemia (ALL) in immunodeficient mice. By contrast, expression of KMT2A-MLLT3 alone cause ALL, double-positive leukemia (DPL, expressing both CD33 and CD19), or bilineal leukemia (BLL, comprised of distinct myeloid and lymphoid leukemia cells), and rarely AML. Further, AML could only be serially propagated with maintained immunophenotype in secondary recipients when cells co-expressed KMT2A-MLLT3 and FLT3-N676K. Consistent with the idea that activated signaling would allow myeloid cells to engraft and maintain their self-renewal capacity, in a secondary recipient, a de novo KRAS-G13D was identified in myeloid cells previously expressing only KMT2A-MLLT3. Gene expression profiling revealed that KMT2A-MLLT3 DPL had a highly similar gene expression profile to ALL, with both expressing key lymphoid transcription factors and ALL cell surface markers, in line with the DPL cells being ALL cells with aberrant expression of CD33. Taken together, our results highlight the need for constitutive active signaling mutations for driving myeloid leukemia in a human xenograft model of KMT2A-R acute leukemia.

2019-04-05 | GSE127492 | GEO

Genome-wide Genotyping of Acute Myeloid Leukemia with Translocation t(9;11)(p22;q23) Reveals Novel Recurrent Genomic Alterations

Project description:To identify cooperating lesions in de novo and therapy-related acute myeloid leukemia (t-AML) with translocation t(9;11)(p22;q23) we performed high-resolution SNP-array profiling on 40 leukemia samples [de novo: n=22; t-AML: n=16; unknown: n=2]. A mean of 1.73 copy number alterations (CNAs)/case were identified with no differences between de novo and t-AML cases. We identified a novel minimally deleted region (MDR) at 7q36.1-q36.2 partly overlapping with a MDR previously identified in core-binding factor AML; MLL3 was the only gene affected in both regions. In addition, a recurrent gain was found at 13q21.33-q22.1 harboring the potential oncogene KLF5. Sequence/expression analysis of selected candidate genes revealed deregulated EVI1 at high frequency (50%). Copy-neutral loss-of-heterozygosity (CN-LOH) was absent in the paired cohort Further analysis of the candidate genes might provide novel insights into the pathogenesis of t(9;11) AML SNP genotyping was performed on 40 de novo and therapy-related MLL-MLLT3-rearranged acute myeloid leukemia samples; Germline control DNA from remission bone marrow or peripheral blood was available for paired analysis in 15 patients. Data were processed using reference alignment, dChipSNP and circular binary segmentation.

2014-05-22 | E-GEOD-46745 | biostudies-arrayexpress

The role of Gaq in MLL leukemogenesis

Project description:Beta-catenin has a central role for self-renewal of leukemic stem cells in Mixed Lineage Leukemia (MLL)-arranged acute myeloid leukemia (AML), however its upstream modulators that can enhance this pathway remain largely unexplored. Through genome-wide gene expression analysis, we identified a previously unknown role for the G protein Gaq in MLL-arranged AML. Inhibition of Gaq reduces the level of active beta-catenin expression and impairs the maintenance of MLL-rearranged AML. Our microarray analysis uncovers a novel functional role for Gaq in leukemia maintenance. GFP-positive leukemic cells flow-sorted by BD Influxâ¢ cell sorter from bone marrow of the primary AML mice induced by MLL-AF9 oncogene were lentivirally transduced with Gaq shRNA (TRCN0000295412, Sigma) or Scrambled control (SHC016, Sigma), and replated in methylcellulose supplemented with IL3. Each group contains triplicate samples.

2016-02-25 | E-MTAB-4078 | biostudies-arrayexpress

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