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Oncogenic Kras synergizes with enhanced TGF-beta-Foxd4 signaling to maintain leukemia-initiating cells in acute myeloid leukemia

ABSTRACT: In this study, the expression profiles of the granulocyte-macrophage progenitor cells (GMP) in bone marrow from KrasG12D/+; CD2Cre mice and wild-type mice were utilized as the in vivo model of acute-myeloid leukemic initiating cells for comparison. We compared the microarray data for transcriptional analysis of the GMP cells from KrasG12D/+; CD2Cre+ mice and littermate control.

ORGANISM(S): Mus musculus

PROVIDER: GSE107326 | GEO | 2017/11/25

SECONDARY ACCESSION(S): PRJNA419770

REPOSITORIES: GEO

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Expression data from AMPK deficient MLL-AF9 leukemia initiating cells and whole leukemia cells

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Oncogenic Kras synergizes with enhanced TGF-beta-Foxd4 signaling to maintain leukemia-initiating cells in acute myeloid leukemia

Project description:Oncogenic Kras synergizes with enhanced TGF-beta-Foxd4 signaling to maintain leukemia-initiating cells in acute myeloid leukemia

| PRJNA419770 | ENA

Cell-Specific Kras and Pten Mutations Document Proliferation Arrest in Granulosa Cells vs. Oncogenic Insult to OSE Cells

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Transcription profiling of human HSC enriched population, common myeloid progenitors, granulocyte macrophage progenitors, megakaryocyte progenitors, and leukemia stem cells (leukemic-GMP) reveals MLL-AF9 transforms committed progenitors to leukemia stem cells by activation of a stem cell program (expt 2)

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Hematopoietic cell differentiation is required for initiation of acute myeloid leukemia

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.

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