Division of Clinical Genetics, Lund University, Lund 22184, Sweden.
Division of Hematology & Oncology, University of Alabama Birmingham, Birmingham, AL 35233, USA.
Cell Rep. 2020 May 26;31(8):107684. doi: 10.1016/j.celrep.2020.107684.
Acute myeloid leukemia (AML) is defined by an accumulation of immature myeloid blasts in the bone marrow. To identify key dependencies of AML stem cells in vivo, here we use a CRISPR-Cas9 screen targeting cell surface genes in a syngeneic MLL-AF9 AML mouse model and show that CXCR4 is a top cell surface regulator of AML cell growth and survival. Deletion of Cxcr4 in AML cells eradicates leukemia cells in vivo without impairing their homing to the bone marrow. In contrast, the CXCR4 ligand CXCL12 is dispensable for leukemia development in recipient mice. Moreover, expression of mutated Cxcr4 variants reveals that CXCR4 signaling is essential for leukemia cells. Notably, loss of CXCR4 signaling in leukemia cells leads to oxidative stress and differentiation in vivo. Taken together, our results identify CXCR4 signaling as essential for AML stem cells by protecting them from differentiation independent of CXCL12 stimulation.
急性髓细胞白血病（AML）的定义是骨髓中积累未成熟髓样细胞。为了确定 AML 干细胞在体内的关键依赖性，我们在这里使用 CRISPR-Cas9 筛选针对同种异体 MLL-AF9 AML 小鼠模型中的细胞表面基因，结果表明 CXCR4 是调节 AML 细胞生长和存活的顶级细胞表面调节剂。AML 细胞中 Cxcr4 的缺失可在不损害其归巢到骨髓的情况下根除体内白血病细胞。相比之下，CXCR4 配体 CXCL12 对于受体小鼠中的白血病发生是可有可无的。此外，表达突变的 Cxcr4 变体表明 CXCR4 信号对于白血病细胞是必需的。值得注意的是，白血病细胞中 CXCR4 信号的丧失会导致体内的氧化应激和分化。总之，我们的结果表明，通过保护白血病细胞免受独立于 CXCL12 刺激的分化，CXCR4 信号对于 AML 干细胞是必需的。
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