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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-10, Vol.73 (19), p.5892-5904
• Main Authors: SIO, Alexander, CHEHAL, Manreet K, TSAI, Kevin, XUELING FAN, ROBERTS, Morgan E, NELSON, Brad H, GREMBECKA, Jolanta, CIERPICKI, Tomasz, KREBS, Danielle L, HARDER, Kenneth W
• Format: Article
• Language: English
• Subjects: Anemia - etiology; Anemia - pathology; Animals; Antineoplastic agents; Biological and medical sciences; Blotting, Western; Bone Marrow - metabolism; Bone Marrow - pathology; Cell Differentiation; Cell Proliferation; Chromatin Immunoprecipitation; DNA Methylation; Epigenomics; Female; Flow Cytometry; Genes, Homeobox - physiology; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Gynecology. Andrology. Obstetrics; Hematopoiesis - genetics; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Histones - metabolism; Leukocytosis - etiology; Leukocytosis - pathology; Male; Mammary gland diseases; Mammary Neoplasms, Experimental - complications; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - pathology; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Pharmacology. Drug treatments; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-13-0842

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 colony-stimulating 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.