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

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

PROVIDER: PRJNA419770 | ENA |

REPOSITORIES: ENA

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Project description:Background: In leukemia, a distinct subpopulation of cancer-initiating cells called leukemia stem cells (LSCs) are believed to drive population expansion and tumor growth. Failing to eliminate LSCs may result in disease relapse regardless of the amount of non-LSCs destroyed. The first step in targeting and eliminating LSCs is to identify and characterize them. Methods: Acute precursor B lymphoblastic leukemia (B-ALL) cells were incubated with fluorescent glucose analog 2-(N-(7-Nitrobenz-2-oxa-1, 3-diazol-4-yl) Amino)-2-Deoxyglucose (NBDG) and sorted based on NBDG uptake. Cell subpopulations defined by glucose uptake were then serially transplanted into mice and evaluated for leukemia initiating capacity. Gene expression profiles of these cells were characterized using RNA-Sequencing (RNA-Seq). Results: A distinct population of NBDG-low cells was identified in patient B-ALL samples. These cells are a small population (1.92% of the entire leukemia population), have lower HLA expression, and are smaller in size (4.0 to 7.0 μm) than NBDG-high cells. All mice transplanted with NBDG-low cells developed leukemia between 5 and 14 weeks, while those transplanted with NBDG-high cells did not develop leukemia (p≤0.0001-0.002). Serial transplantation of the NBDG-low mouse model resulted in successful leukemia development. NBDG-medium (NBDG-med) populations also developed leukemia. Interestingly, comprehensive molecular characterization of NBDG-low and -med cells from patient-derived xenograft models using RNA-Seq revealed a distinct profile of 2,162 differentially-expressed transcripts (DETs) (p<0.05) with 70.6% down-regulated in the NBDG-low cells. Hierarchical clustering of DETs showed distinct segregation of NBDG-low from the NBDG-med and -high groups with a number of marked transcription expression alterations in the NBDG-low group consistent with cancer survival. Conclusions: A unique subpopulation of cells with low glucose uptake (NBDG-low) in B-ALL was discovered. These cells, despite their quiescence characteristics, once transplanted in mice, showed potent leukemia initiating capacity. Although NBDG-med cells also showed leukemia initiating capacity, gene expression profiling revealed a distinct signature that clearly distinguishes NBDG-low cells from NBDG-med and the rest of the leukemia populations. These results suggest that NBDG-low cells may represent quiescent LSCs. These cells can be activated in the appropriate environment in vivo, showing leukemia initiating capacity. Our study provides insight into the biologic mechanisms of B-ALL initiation and/or survival.

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

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