Allogeneic hsct with reduced intensity conditioning regimens in high risk patients with myelofibrosis

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The constitutive mobilization of bone marrow-repopulating cells into the peripheral blood in idiopathic myelofibrosis

AbstractIdiopathic myelofibrosis (IM) is characterized by the constitutive mobilization of CD34+ cells. IM peripheral blood (PB) CD34+ cells had a reduced cloning efficiency and a lower frequency of cobblestone areas compared with normal granulocyte colony-stimulating factor (G-CSF)-mobilized PB CD34+ cells. IM CD34+ cells engrafted nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, demonstrating that they contain bone marrow (BM)-repopulating cells. G-CSF-mobilized CD34+ cells produced multiple hematopoietic lineages within the NOD/SCID mice with a predominance of CD19+ cells. By contrast, IM CD34+ cells produced predominantly CD33+ cells, increased numbers of CD41+ cells, but fewer CD19+ cells. Transcriptional clonality assays of the engrafted human IM cells demonstrated their clonal origin. CD34+ cells from one patient isolated prior to leukemic transformation were capable of generating acute leukemia in NOD/SCID mice. The engrafted human cells exhibited the same abnormal karyotype as primary cells in a portion of the population. These findings demonstrate that BM-repopulating cells and more differentiated progenitor cells are constitutively mobilized into the PB in IM, and that their differentiation program is abnormal. In addition, the NOD/SCID model may be useful in gaining an understanding of the events occurring during the transition of IM to acute leukemia. (Blood. 2005;105:1699-1705

Constitutive mobilization of CD34+ cells into the peripheral blood in idiopathic myelofibrosis may be due to the action of a number of proteases

Abstract Idiopathic myelofibrosis (IM) is characterized by increased numbers of CD34+ cells in the peripheral blood (PB). We explored the possible mechanisms underlying this abnormal trafficking of CD34+ cells. Plasma levels of neutrophil elastase (NE), total and active matrix metalloproteinase 9 (MMP-9), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were dramatically increased in IM. The absolute number of CD34+ cells in the PB was correlated with the levels of sVCAM-1. Marked elevations of the levels of NE but not total and active MMP-9 as well as MMP-2 were detected in media conditioned by IM mononuclear cells (MNCs) as compared with that of healthy volunteers. IM MNC-conditioned media, however, was shown by zymographic analysis to contain increased gelatinolytic activity corresponding to the molecular weight of MMP-9. IM MNC-conditioned media also exhibited a greater ability to cleave VCAM-1 and c-kit in vitro, consistent with the biologic actions of NE. In addition, the increased ability of IM PB CD34+ cells to migrate through a reconstituted basement membrane was diminished by several inhibitors of MMP-9 activity, indicating that these cells express increased levels of this MMP. These data indicate that a proteolytic environment exists in IM which might result in the sustained mobilization of CD34+ cells

The constitutive mobilization of bone marrow-repopulating cells into the peripheral blood in idiopathic myelofibrosis

Idiopathic myelofibrosis (IM) is characterized by the constitutive mobilization of CD34(+) cells. IM peripheral blood (PB) CD34(+) cells had a reduced cloning efficiency and a lower frequency of cobblestone areas compared with normal granulocyte colony-stimulating factor (G-CSF)-mobilized PB CD34(+) cells. IM CD34(+) cells engrafted nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, demonstrating that they contain bone marrow (BM)-repopulating cells. G-CSF-mobilized CD34(+) cells produced multiple hematopoietic lineages within the NOD/SCID mice with a predominance of CD19(+) cells. By contrast, IM CD34(+) cells produced predominantly CD33(+) cells, increased numbers of CD41(+) cells, but fewer CD19(+) cells. Transcriptional clonality assays of the engrafted human IM cells demonstrated their clonal origin. CD34(+) cells from one patient isolated prior to leukemic transformation were capable of generating acute leukemia in NOD/SCID mice. The engrafted human cells exhibited the same abnormal karyotype as primary cells in a portion of the population. These findings demonstrate that BM-repopulating cells and more differentiated progenitor cells are constitutively mobilized into the PB in IM, and that their differentiation program is abnormal. In addition, the NOD/SCID model may be useful in gaining an understanding of the events occurring during the transition of IM to acute leukemia