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 NOW/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. [Cancer Res 2009;69(19):7612-8]