Dysregulated Hematopoiesis Caused by Mammary Cancer Is Associated with Epigenetic Changes and Hox Gene Expression in Hematopoietic Cells

Abstract

Cancer is associated with immune dysfunction characterized by the presence of proinflammatory and immunosuppressive cells and factors that contribute to tumor growth and progression. Here we show that mammary tumor growth is associated with defects in hematopoiesis, leading to myeloproliferative-like disease (leukemoid reaction), anemia, and disruption of the bone marrow stem/progenitor compartment. The defects we characterized included impaired erythropoiesis, leukocytosis, loss of early progenitor cells in the bone marrow, and splenic extramedullary hematopoiesis. We established an in vitro model to dissect interactions between mammary cancers and the hematopoietic system. Investigations in this model revealed that granulocyte colonystimulating factor (G-CSF) produced by mammary tumors can synergize with FLT3L and granulocyte macrophage CSF (GM-CSF) to expand myeloid progenitors and their progeny in culture. Mammary tumor growth was associated with histone methylation changes within lineage-negative c-Kit-positive hematopoietic cells within the bone marrow of tumor-bearing mice. Similarly, parallel histone methylation patterns occurred in cultured bone marrow cells exposed to mammary tumor-conditioned cell culture media. Notably, changes in histone methylation in these cell populations correlated with dysregulated expression of genes controlling hematopoietic lineage commitment and differentiation, including Hox family genes and members of the Polycomb repressive complex 2 (PRC2) chromatin-remodeling complex. Together, our results show that mammary tumor-secreted factors induce profound perturbations in hematopoiesis and expression of key hematopoietic regulatory genes.

VEGF-A/VEGFR Inhibition Restores Hematopoietic Homeostasis in the Bone Marrow and Attenuates Tumor Growth

“…Bone marrow from tumor-bearing MMTV-PyT mice displayed an increase in the percentage (data not shown) and absolute number (Fig. 3A) of LKS HSPCs, consistent with recent work in the MMTVneu OTI/OTII model (7). In contrast to the study by Sio and colleagues (7), there was no evidence of increased extramedullary hematopoiesis in this model, with constant numbers of nucleated cells and LKS HSPCs in the spleen at all tumor volumes (data not shown).…”

“…4D). We confirm recent work showing that primary tumors are able to communicate long-distance with HSPCs in the bone marrow (7). Although the effect of other tumor-derived factors cannot be ruled out, this communication appears to be mediated by the effects of circulating VEGF-A on the sinusoidal vasculature of the bone marrow, as targeting of vascularspecific VEGF receptors can reverse the aberrant entrance of HSPCs into proliferative and differentiative phases of the cell cycle.…”

“…HSPC-derived cells can be recruited to distant organs where they promote metastasis, as well as into primary tumors (4). Systemic conditions such as diabetes and estradiol treatment can target the subset of bone marrow HSPCs capable of reconstituting the hematopoietic system (5,6), and recent work shows that tumor burden increases bone marrow HSPC numbers (7), raising the possibility that an important source of HSPC-derived cells recruited by tumors may be the niches of the bone marrow.…”

2B4-SAP signaling is required for the priming of naive CD8+ T cells by antigen-expressing B cells and B lymphoma cells

“…37 After 4 d culture, WT and Sh2d1a ¡/¡ CD8 C T cells exhibited comparable levels of proliferation and differentiation into secreting IFNg effectors (Fig. 4C).…”

SOCS3 Deficiency in Myeloid Cells Promotes Tumor Development: Involvement of STAT3 Activation and Myeloid-Derived Suppressor Cells

“…4A). Perturbed myelopoiesis and spleen hematopoiesis (36) may account for the accumulation of Gr-1 + CD11b + cells in tumors and increased spleen size. EdU cell proliferation assays were performed to address the role of SOCS3 on myeloid cell proliferation.…”