Abstract
Acute T-cell lymphoblastic leukemia/lymphoma (T-ALL) is an aggressive hematopoietic malignancy affecting both children and adults. Previous studies of T-ALL mouse models induced by different genetic mutations have provided highly diverse results on the issues of T-cell leukemia/lymphoma-initiating cells (T-LICs) and potential mechanisms contributing to T-LIC transformation. Here, we show that oncogenic Kras (Kras G12D) expressed from its endogenous locus is a potent inducer of T-ALL even in a less sensitized BALB/c background. Notch1 mutations, including exon 34 mutations and recently characterized type 1 and 2 deletions, are detected in 100% of Kras G12D-induced T-ALL tumors. Although these mutations are not detected at the pre-leukemia stage, incremental up-regulation of NOTCH1 surface expression is observed at the pre-leukemia and leukemia stages. As secondary genetic hits in the Kras G12D model, Notch1 mutations target CD8(+) T-cells but not hematopoietic stem cells to further promote T-ALL progression. Pre-leukemia T-cells without detectable Notch1 mutations do not induce T-ALL in secondary recipient mice compared with T-ALL tumor cells with Notch1 mutations. We found huge variations in T-LIC frequency and immunophenotypes of cells enriched for T-LICs. Unlike Pten deficiency-induced T-ALL, oncogenic Kras-initiated T-ALL is not associated with up-regulation of the Wnt/β-catenin pathway. Our results suggest that up-regulation of NOTCH1 signaling, through either overexpression of surface NOTCH1 or acquired gain-of-function mutations, is involved in both T-ALL initiation and progression. Notch1 mutations and Kras G12D contribute cooperatively to leukemogenic transformation of normal T-cells.
Highlights
Endogenous oncogenic Kras induces a highly penetrant acute T-cell lymphoblastic leukemia/lymphoma (T-ALL)
In recipient mice transplanted with Kras G12D bone marrow cells, BALB/c mice survived significantly longer than B6 mice (Fig. 1A), the disease penetrance and phenotypes in the BALB/c background were very similar to those in the B6 background (Fig. 1, B–D), suggesting that Kras G12D is a potent inducer of T-ALL in both genetic backgrounds
Notch1 Mutations Are Identified in 100% of Kras G12D-induced T-ALL Tumors—To better understand the mechanisms of Kras G12D-initiated T-ALL, we characterized recipient animals transplanted with Kras G12D bone marrow cells at 4 or 8 weeks or at a moribund stage (ϳ12 weeks) after transplantation (Fig. 2)
Summary
Endogenous oncogenic Kras induces a highly penetrant acute T-cell lymphoblastic leukemia/lymphoma (T-ALL). Results: Up-regulation of NOTCH1 signaling, through either overexpression of surface NOTCH1 or acquired gain-of-function mutations, is involved in both T-ALL initiation and progression. Previous studies of T-ALL mouse models induced by different genetic mutations have provided highly diverse results on the issues of T-cell leukemia/lymphomainitiating cells (T-LICs) and potential mechanisms contributing to T-LIC transformation. Notch mutations, including exon 34 mutations and recently characterized type 1 and 2 deletions, are detected in 100% of Kras G12D-induced T-ALL tumors These mutations are not detected at the pre-leukemia stage, incremental up-regulation of NOTCH1 surface expression is observed at the pre-leukemia and leukemia stages. Our results suggest that up-regulation of NOTCH1 signaling, through either overexpression of surface NOTCH1 or acquired gain-of-function mutations, is involved in both T-ALL initiation and progression. Notch mutations and Kras G12D contribute cooperatively to leukemogenic transformation of normal T-cells
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