We studied the relationship between granulocyte JAK2 (V617F) mutation status, circulating CD34 ؉ cells, and granulocyte activation in myeloproliferative disorders. Quantitative allele-specific polymerase chain reaction (PCR) showed significant differences between various disorders with respect to either the proportion of positive patients (53%-100%) or that of mutant alleles, which overall ranged from 1% to 100%. In polycythemia vera, JAK2 (V617F) was detected in 23 of 25 subjects at diagnosis and in 16 of 16 patients whose disease had evolved into myelofibrosis; median percentages of mutant alleles in these subgroups were significantly different (32% versus 95%, P < .001). Circulating CD34 ؉ cell counts were variably elevated and associated with disease category and JAK2 (V617F) mutation status. Most patients had granulocyte activation patterns similar to those induced by administration of granulocyte colonystimulating factor. A JAK2 (V617F) gene dosage effect on both CD34 ؉ cell counts and granulocyte activation was clearly demonstrated in polycythemia vera, where abnormal patterns were mainly found in patients carrying more than 50% mutant alleles. These observations suggest that JAK2 ( IntroductionPhiladelphia-negative (Ph Ϫ ) chronic myeloproliferative disorders include polycythemia vera (PV), essential thrombocythemia (ET), and chronic idiopathic myelofibrosis (CIMF). 1 Diagnostic criteria for these conditions were been redefined a few years ago by the World Health Organization (WHO) classification, 2 which considers bone marrow biopsy as an essential procedure for diagnosis of ET and CIMF and as a complementary procedure for diagnosis of PV. According to the WHO criteria, CIMF can be subdivided into a prefibrotic stage (p-CIMF) and a fibrotic stage (f-CIMF); from a clinical standpoint, the p-CIMF mimics ET. 3 A gain-of-function mutation of the Janus kinase 2 (JAK2) gene has been recently reported in myeloproliferative disorders. [4][5][6][7][8] The currently available data indicate that JAK2 (V617F) participates in the pathogenesis of these conditions. 6 Although the mutation's precise place in the hierarchical order of events remains to be established, gain of function and loss of control appear to be the essential features of the excessive myeloproliferation associated with JAK2 (V617F). 9 Abnormal trafficking of CD34 ϩ cells with increased counts in the peripheral blood is found not only in CIMF but also in advanced stages of PV and ET. [10][11][12] It has been recently demonstrated that bone marrow-repopulating cells and more differentiated progenitor cells are constitutively mobilized into the peripheral blood in CIMF and that their differentiation program is abnormal. 13 Additional studies have suggested that the marrow milieu of patients with CIMF is characterized by a proteolytic environment that contributes to CD34 ϩ cell mobilization. 14 Activation of signaling by the JAK2 (V617F) mutation is associated with altered gene expression in granulocytes from patients with myeloproliferative disorde...
The purpose of this study was to develop a flow cytometric approach to the evaluation of marrow dysplasia in myelodysplastic syndromes (MDS). We first studied a cohort of 103 MDS patients as well as 46 pathological and healthy controls. Flow cytometry data were expressed as percentage of positive cells. Analysis of erythroid cells showed higher proportions of immature cells (Po0.001) and decreased levels of CD71 expression on nucleated red cells (P ¼ 0.02) in MDS. Analysis of myeloid cells showed lower proportions of CD10 þ and higher proportions of CD56 þ granulocytes (Po0.001), and increased ratios of immature to mature cells (P ¼ 0.007). Since no single immunophenotype could accurately differentiate MDS from other conditions, we used discriminant analysis for generating erythroid and myeloid classification functions using combinations of immunophenotypic parameters. These functions were prospectively validated in a testing cohort of 69 MDS patients and 46 pathological controls. A diagnosis of MDS was obtained in 60/69 cases (87%). No false-positive results were noticed among controls. Significant correlations between values of these functions and both degree of morphological dysplasia and the International Prognostic Scoring System were found. These findings indicate that flow cytometry evaluation of marrow dysplasia is feasible and may be useful in the work-up of individual MDS patients.
This study indicates that a thorough investigation of family history should be part of the initial work-up of patients with CMDs. Patients with familial CMDs show the same clinical features and suffer the same complications as patients with sporadic disease. Age distribution between parent and offspring and telomere length shortening provide evidence of disease anticipation.
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