Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan;
Department of Immune Regulation, Tokyo Medical and Dental University, Tokyo, Japan;
Blood. 2016 May 26;127(21):2607-17. doi: 10.1182/blood-2015-10-673087. Epub 2016 Mar 22.
Basophilia is a frequently observed hematological abnormality in chronic myeloid leukemia (CML), but its pathophysiological roles are undefined. We previously demonstrated that an inflammatory chemokine, CCL3, preferentially acts on normal hematopoietic stem/progenitor cells and crucially contributes to the maintenance of leukemia initiating cells (LICs) in bone marrow (BM) during the initiation process of CML. However, the major cellular source of CCL3 in BM and the precise mechanism of CCL3-mediated maintenance of LICs remain to be investigated. To delineate the cellular process facilitating this CCL3-mediated crosstalk between normal and leukemic hematopoiesis, we precisely examined CCL3-expressing cells and their functions in both normal hematopoiesis and CML leukemogenesis. Herein, we demonstrate that basophils can constitutively express CCL3 to negatively regulate the normal hematopoietic process, especially hematopoietic reconstitution after BM transplantation. Moreover, CCL3-expressing basophil-like leukemia cells were found to accumulate in CML BM and supported the predominant expansion of LICs therein. These observations suggest that intra-BM basophil expansion can favor leukemia-tropic hematopoiesis in CML by providing CCL3, a potent inhibitor of normal hematopoiesis and that basophil-derived CCL3 may be a novel target molecule for the treatment of CML.
嗜碱性粒细胞是慢性髓系白血病（CML）中经常观察到的血液学异常，但它的病理生理作用尚未确定。我们之前的研究表明，一种炎症趋化因子 CCL3 优先作用于正常造血干/祖细胞，并在 CML 起始过程中对骨髓（BM）中白血病起始细胞（LICs）的维持起着至关重要的作用。然而，BM 中 CCL3 的主要细胞来源以及 CCL3 介导 LIC 维持的确切机制仍有待研究。为了阐明促进这种 CCL3 介导的正常和白血病造血之间串扰的细胞过程，我们精确地检查了 CCL3 表达细胞及其在正常造血和 CML 白血病发生中的功能。在此，我们证明嗜碱性粒细胞可以组成性地表达 CCL3，从而负调控正常造血过程，特别是 BM 移植后的造血重建。此外，发现表达 CCL3 的嗜碱性粒细胞样白血病细胞在 CML BM 中积聚，并支持其中 LIC 的主要扩增。这些观察结果表明，BM 内嗜碱性粒细胞的扩张可以通过提供 CCL3 来促进 CML 中的白血病倾向性造血，CCL3 是正常造血的有效抑制剂，而嗜碱性粒细胞衍生的 CCL3 可能是 CML 治疗的新靶标分子。
