title: Correction of the abnormal trafficking of primary myelofibrosis CD34+ cells by treatment with chromatin-modifying agents.
abstract: The abnormal trafficking of CD34+ cells is a unique characteristic of primary myelofibrosis (PMF). We have further studied the behavior of PMF CD34+ cells by examining their homing to the marrow and the spleens of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Following the infusion of PMF and normal granulocyte colony-stimulating factor-mobilized peripheral blood (mPB) CD34+ cells into NOD/SCID mice, reduced numbers of PMF CD34+ cells and granulocyte-macrophage colony-forming unit (CFU-GM) compared with mPB were detected in the marrow of these mice, whereas similar numbers of PMF and mPB CD34+ cells and CFU-GM homed to their spleens. The abnormal homing of PMF CD34+ cells was associated with reduced expression of CXCR4, but was not related to the presence of JAK2V617F. The sequential treatment of PMF CD34+ cells with the chromatin-modifying agents 5-aza-2'-deoxycytidine (5azaD) and trichostatin A (TSA), but not treatment with small molecule inhibitors of JAK2, resulted in the generation of increased numbers of CD34+CXCR4+ cells, which was accompanied by enhanced homing of PMF CD34+ cells to the marrow but not the spleens of NOD/SCID mice. Following 5azaD/TSA treatment, JAK2V617F-negative PMF hematopoietic progenitor cells preferentially homed to the marrow but not the spleens of recipient mice. Our data suggest that PMF CD34+ cells are characterized by a reduced ability to home to the marrow but not the spleens of NOD/SCID mice and that this homing defect can be corrected by sequential treatment with chromatin-modifying agents.
authors.affiliation: Division of Hematology/Oncology, Tisch Cancer Institute, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Takefumi
authors.initials: T
authors.lastname: Ishii
authors.forename: Selcuk
authors.initials: S
authors.lastname: Sozer
authors.forename: Jiapeng
authors.initials: J
authors.lastname: Wang
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Xu
authors.forename: Ronald
authors.initials: R
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001853:Bone Marrow / Q000473:pathology; D002843:Chromatin / Q000187:drug effects*; D000077209:Decitabine; D015536:Down-Regulation; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D013154:Spleen / Q000473:pathology
chemical_list: D018952:Antigens, CD34; C527276:CXCR4 protein, human; D002843:Chromatin; D006877:Hydroxamic Acids; D019718:Receptors, CXCR4; C012589:trichostatin A; D000077209:Decitabine; D001374:Azacitidine