Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders

Abstract

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...

Effects of the JAK2 mutation on the hematopoietic stem and progenitor compartment in human myeloproliferative neoplasms

“…Indeed, PB from MPN patients has previously been demonstrated to contain an increased CD34 ϩ fraction compared with normal PB. 17 In contrast to PV and ET, the alterations in the size of the HSC and GMP population and the stable allele burden in JAK2 V617F-positive MF suggest an alteration in the regulation of the HSPC compartment through additional mechanisms, such as the presence of other mutations, microenvironment effects, and/or genetic modifiers. These findings are also in consonance with functional differences between human PV and MF V617F mutant HSCs as detected in xenotransplant experiments.…”

Interferon-α therapy in bcr-abl-negative myeloproliferative neoplasms

“…For example, the percentage of the circulating mutated JAK2 allele was shown to be significantly higher in PV and ET patients who developed myelofibrosis, and may also be significantly higher in patients who develop vascular complications. 90,91 Some authors suggested that IFN-a could delay myelofibrosis development in PV patients 42 based on in vitro data, a benefit that could be mediated by reduction of the proportion of JAK2V617F mutated cells. In addition, the selective effect of IFN-a on mutated granulocytes may affect the incidence of thrombosis, as it has been shown that leukocyte SPOTLIGHT activation and hemostatic changes were correlated with the presence of JAK2 mutation.…”

Aberrant signal transduction pathways in myeloproliferative neoplasms

“…104 The release of CD34( þ ) cells is generally due to a combination of increased levels of proteases 105 and especially due to the downregulation of the CXCR4 receptor on CD34( þ ) cells. 106 An altered SDF-1/CXCR4 axis was demonstrated in PMF patients with CD34( þ ) cells in the periphery.…”