The JAK2-V617F mutation is frequently present at diagnosis in patients with essential thrombocythemia and polycythemia vera

Abstract

We determined the allelic frequency of the JAK2-V617F mutation in DNA and assessed the expression levels of the mutant and wild-type JAK2 mRNA in granulocytes from 60 patients with essential thrombocythemia (ET) and 62 patients with polycythemia vera (PV) at the time of diagnosis. Using allele-specific quantitative polymerase chain reaction (qPCR), we detected JAK2-V617F in 75% of ET and 97% of PV at diagnosis. The total JAK2 mRNA levels were elevated in ET, PV, and secondary and idiopathic erythrocytosis, suggesting that hyperactive hematopoiesis alters JAK2 expression. The expression levels of JAK2-V617F mRNA were variable but strongly correlated with the allelic ratio of JAK2-V617F determined in DNA. Thus, differences in JAK2-V617F expression, markedly lower in ET than in PV, reflected different percentages of granulocytes carrying the mutation. Moreover, allelic ratios higher than 50% JAK2-V617F, indicating the presence of granulocytes homozygous for JAK2-V617F, were found in 70% of PV at diagnosis but never in

A prospective study of 338 patients with polycythemia vera: the impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications

“…10,11,[24][25][26][27] In fact, a significant direct correlation was found between the proportion of mutant alleles and hemoglobin level and WBC count, while there was an inverse relationship with platelet count. A pathophysiological basis for these relationships has been provided by experimental studies.…”

“…This is in keeping with previous observations based on the use of sensitive detection methods. 10,[20][21][22][23] However, there was a small subgroup of patients who satisfied the WHO criteria for diagnosis of PV, but were consistently negative for JAK2 mutations on granulocytes. Our quantitative reverse transcriptase-PCR-based allelic discrimination assay for JAK2 (V617F) has now a detection limit of 0.2% mutant alleles, while direct sequencing applied for JAK2 exon 12 mutations of 10% mutant alleles.…”

JAK2 mutation and disease phenotype: a double L611V/V617F in cis mutation of JAK2 is associated with isolated erythrocytosis and increased activation of AKT and ERK1/2 rather than STAT5

“…9 Verification of the mutational burden using pyrosequencing detected 20% JAK2-V617F. 10 Cloning and sequencing analysis of exon 14 of JAK2 revealed an additional mutation of base 1831 (1831T4G), changing leucine 611 for a valine (L611V) (Figure 1a).…”

“…DNA and RNA extracted from purified granulocytes, platelets, CD3 þ T-lymphocytes and colonies were analyzed using allele-specific quantitative PCR assays (AS-qPCRs), pyrosequencing and conventional sequencing. [9][10][11] The primers and probes used are listed in Supplementary Table 1. With informed consent, DNA samples from 10 healthy donors, 199 control patients with idiopathic erythrocytosis (n ¼ 22), secondary erythrocytosis (n ¼ 148) or splanchnic vein thrombosis (n ¼ 29), and 465 patients diagnosed following the 2002 WHO criteria with PV (n ¼ 168), ET (n ¼ 271) or primary myelofibrosis (n ¼ 26) were analyzed, as were DNA from 31 archival samples from MPN transformed into acute myeloid leukemia.…”

Comparison of mutated ABL1 and JAK2 as oncogenes and drug targets in myeloproliferative disorders

“…First, not a single patient has been identified who was JAK2V617F-negative at the time of MPD diagnosis, but became JAK2V617F later during the disease course of the disease. 154 Second, JAK2V617F as a single agent rapidly gives rise to a PV-like disease in murine models 12,53,93 in a similar way by which BCR-ABL1 gives rise to a CML-like disease. Although it is impossible to be absolutely certain, most people in the field consider that chronic-phase CML is a one-hit disease, that is, BCR-ABL1 is the sole abnormality.…”