Correction of the abnormal trafficking of primary myelofibrosis CD34 ⁺ cells by treatment with chromatin-modifying agents

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.