Idiopathic myelofibrosis (IM) is characterized by increased numbers of CD34
IntroductionChronic idiopathic myelofibrosis (IM) is a hematological malignancy characterized by splenomegaly, a leukoerythroblastic blood picture, teardrop poikilocytosis (dacrocytosis), varying degrees of bone marrow (BM) fibrosis, and extramedullary hematopoiesis. [1][2][3][4] IM is thought to originate at the level of the multipotent hematopoietic stem cell (HSC). [1][2][3][4] The HSC defect results in a profound hyperplasia of morphologically abnormal megakaryocytes and clonal populations of monocytes, which have been shown to locally release fibrogenic growth factors, leading to BM fibrosis. [5][6][7] Rare CD34 ϩ HSC/hematopoietic progenitor cells (HPCs) circulate in the peripheral blood (PB) of healthy individuals. [8][9] Increased numbers of CD34 ϩ cells can be mobilized into the PB following the administration of a variety of cytokines and/or chemotherapeutic agents. [9][10][11] Barosi et al recently demonstrated that the PB of IM patients contained 360 times more CD34 ϩ cells than normal controls and 18 to 30 times more CD34 ϩ cells than patients with other Philadelphia chromosome-negative (Ph -) myeloproliferative disorders (MPDs). 12 In addition, the PB CD34 ϩ cell number was further shown to be related to disease progression and to serve as a biomarker for disease activity. 12 The number of assayable HPCs present in the PB of IM patients have also been shown to be increased. [13][14][15] Therefore, IM represents a unique situation in which the numbers of CD34 ϩ cells appearing in the PB are frequently markedly increased in the absence of extrinsic stimuli.Although the CD34 antigen is expressed by both the HSC and HPC, the functional potential of the CD34 ϩ cells in the PB of IM patients has not been well defined. In this report we have further phenotyped the CD34 ϩ cells of IM patients and examined the multilineage differentiation potential of these cells, as well as their ability to repopulate immunodeficient mice. In addition, we have demonstrated the utility of this in vivo model to analyze the cellular and molecular events that occur during the transition of IM to acute leukemia. Patients, materials, and methods Patients and healthy control subjectsAll human tissue samples were obtained after informed consent following the guidelines of the institutional review board of the University of Illinois College of Medicine. PB samples were obtained from: (1) healthy donors in steady-state hematopoiesis; (2) healthy donors mobilized with granulocyte colony-stimulating factor (G-CSF; Amgen, Thousand Oaks, CA) at 5 g/kg/d subcutaneously; and (3) patients with IM or polycythemia vera (PV) who met the World Health Organization (WHO) diagnostic criteria for IM and PV, [1][2][3][4]16 as well as patients with secondary myelofibrosis associated with pulmonary hypertension. 17 None of the patients were receiving cytotoxic agents at the time of study and none had evidence of transformation to acute leukemia. The specific clinical characteristics of the patients whose CD34 ϩ cells were examined for BM-repopulati...
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