Accumulating evidence suggests that an inflammatory chemokine, CCL3, has multiple functions in hematopoietic system besides its pro-inflammatory activities. CCL3 can in vitro inhibit the proliferation of hematopoietic stem/progenitor cells (HSPCs). Based on this unique function, CCL3 is alternatively called as “stem cell inhibitor”. Thus, CCL3 can potentially influence the homeostasis of HSPCs. In sharp contrast, CCL3 hardly affects leukemia initiating cells (LICs) in chronic myeloid leukemia (CML) although they share several characteristic capabilities including self-renewal and cellular quiescence, with normal HSPCs. Thus, CCL3 can be a potent mediator to induce the dominant proliferation of LICs in the CML BM. However, there is a dearth of studies precisely demonstrating the major cellular source of CCL3 in BM and the contribution of endogenously-produced CCL3 to the CML pathophysiology.
Basophilia is a frequently observed hematological abnormality in CML but its pathophysiological roles are undefined. Herein, our meticulous examination of CCL3-expressing cells in CML BM revealed that basophil-like leukemia cells are a major cellular source of CCL3. Moreover, CCL3-expressing basophil-like leukemia cells accumulated in CML BM and basophil-derived CCL3 preferentially acted on the normal HSPCs, resulting in their suppressed proliferation. As a consequence, LICs expanded dominantly in BM during the initiation process of CML. Indeed, the ablation of CCL3 or the depletion of basophils markedly retarded the CML development in mouse CML model. These observations would imply 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 can be a novel target molecule for the treatment of CML.