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Niche TWIST1 is critical for maintaining normal hematopoiesis and impeding leukemia progression.

ABSTRACT: The bone marrow microenvironment regulates normal and malignant hematopoiesis, but the underlying molecular mechanisms remain poorly defined. Using a chimeric mice model, we demonstrate that Twist1 deletion in the bone marrow microenvironment results in alteration of multiple niche cells as well as downregulated expression of major hematopoietic stem cell supportive factors. The perturbed microenvironment reduces hematopoietic stem cell homing and retention, impairs hematopoietic stem cell self-renewal and induces myeloid skewing. Nevertheless, it accelerates the progression of MLL-AF9 leukemia, which is partially mediated by Jagged-2-dependent Notch signaling. Our data provide the first demonstration of a pivotal role of TWIST1 in favoring normal hematopoiesis and hampering leukemia development. They also bring new insights into the role of the bone marrow niche in driving the development of acute myeloid leukemia, and suggest possible new avenues, exploiting the niche, to improve leukemia treatments.

SUBMITTER: Liu X

PROVIDER: S-EPMC6269292 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Niche TWIST1 is critical for maintaining normal hematopoiesis and impeding leukemia progression.

Liu Xiaoyan X Ma Yanping Y Li Rongrong R Guo Dan D Wang Nan N Zhao Yangyang Y Yin Jing J Ren Qian Q Lin Yongmin Y Ma Xiaotong X

Haematologica 20180719 12

The bone marrow microenvironment regulates normal and malignant hematopoiesis, but the underlying molecular mechanisms remain poorly defined. Using a chimeric mice model, we demonstrate that <i>Twist1</i> deletion in the bone marrow microenvironment results in alteration of multiple niche cells as well as downregulated expression of major hematopoietic stem cell supportive factors. The perturbed microenvironment reduces hematopoietic stem cell homing and retention, impairs hematopoietic stem cel ...[more]

PMID: 30026340

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Project description:BackgroundCD36 has been identified as a potential therapeutic target both in leukemic cells and in the tumor immune microenvironment. In acute myeloid leukemia (AML), we found that APOC2 acts with CD36 to promote leukemia growth by activating the LYN-ERK signaling. CD36 also plays a role in lipid metabolism of cancer associated T-cells leading to impaired cytotoxic CD8+ T-cell and enhanced Treg cell function. To establish CD36 as a viable therapeutic target in AML, we investigated whether targeting CD36 has any detrimental impact on normal hematopoietic cells.MethodsDifferential expression data of CD36 during human and mouse normal hematopoiesis were examined and compared. Cd36 knockout (Cd36-KO) mice were evaluated for blood analysis, hematopoietic stem cells and progenitors (HSPCs) function and phenotype analyses, and T cells in vitro expansion and phenotypes in comparison with wild type (WT) mice. In addition, MLL-PTD/FLT3-ITD leukemic cells were engrafted into Cd36-KO and WT mice, and leukemia burden was compared between groups.ResultsRNA-Seq data showed that Cd36 expression was low in HSPCs and increased as cells matured. Phenotypic analysis revealed limited changes in blood count except for a slight yet significantly lower red blood cell count and hemoglobin and hematocrit levels in Cd36-KO mice compared with WT mice (P < 0.05). In vitro cell proliferation assays of splenocytes and HSPCs from Cd36-KO mice showed a similar pattern of expansion to that of cells from WT mice. Characterization of HSPCs showed similar percentages of the different progenitor cell populations between Cd36-KO with WT mice. However, Cd36-KO mice exhibited ~ 40% reduction of the number of colonies developed from HSPCs cells compared with WT mice (P < 0.001). Cd36-KO and WT mice presented comparably healthy BM transplant in non-competitive models and developed similar leukemia burden.ConclusionsAlthough the loss of Cd36 affects the hematopoietic stem cell and erythropoiesis, limited detrimental overall impact was observed on normal Hematopoietic and leukemic microenvironments. Altogether, considering the limited impact on normal hematopoiesis, therapeutic approaches to target CD36 in cancer are unlikely to result in toxicity to normal blood cells.

Dataset Information

Niche TWIST1 is critical for maintaining normal hematopoiesis and impeding leukemia progression.

Publications

Niche TWIST1 is critical for maintaining normal hematopoiesis and impeding leukemia progression.

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