Multipotent Progenitor-3 Cells Are Reprogrammed by Bone-derived DKK1 to Drive Myelopoiesis in Breast Cancer

The expansion of immunosuppressive myeloid cells drives tumor progression, yet clinical strategies aimed at depleting these populations have shown limited effects and high toxicity. Because myeloid cells arise from hematopoietic progenitors, we asked whether solid tumors durably reprogram hematopoietic stem and progenitor cells (HSPCs) to sustain pathological myeloid bias. Here, we show treatment-naïve stage-III breast cancer (BC) patients and murine models of primary BC exhibited expansion of bone marrow HSPCs with enhanced myeloid output. Transplantation assays further demonstrated that tumor-educated HSPCs retained durable myeloid bias following transfer into healthy recipients and promoted tumor progression upon secondary challenge, accompanied by selective expansion of multi-potent progenitors (MPPs) and mature myeloid cells. In contrast, transplantation of long-term HSCs did not confer durable hematopoietic changes or enhanced tumor growth, indicating that tumor-induced myeloid bias is mediated by downstream progenitors. Consistently, depletion of mature myeloid cells did not alter HSCs but triggered rapid MPP expansion and myeloid rebound in tumor-bearing mice compared to no-tumor controls. Among progenitor subsets, MPP3s emerged as the principal drivers of tumor-associated myelopoiesis. Single-cell RNA sequencing of BC patient bone marrow revealed reduced Wnt-β-catenin signaling in HSPCs and identified DKK1, a bone-derived Wnt inhibitor elevated during BC progression, as a mediator of MPP3 reprogramming. Targeting bone-derived DKK1 limited HSPC engraftment following transplantation into naïve mice, and reduced BC progression, MPP3 expansion, and myeloid output in tumor bearing mice. These findings highlight solid tumor-induced hematopoietic reprogramming and identify bone-derived DKK1 as a regulator of MPP3 fate.