Respective clustering of unfavorable and favorable cytogenetic clones in myelofibrosis with myeloid metaplasia with homozygosity for JAK2^V617F and response to erythropoietin therapy

Abstract

BACKGROUNDPatients who have myelofibrosis with myeloid metaplasia (MMM) display recurrent, albeit nonspecific cytogenetic abnormalities that are diverse prognostically. For the current study, the authors explored the relation between specific cytogenetic clones and JAK2V617F mutational status in patients with MMM and the effects on treatment response to erythropoietin (Epo).METHODSConcomitantly collected blood granulocytes and bone marrow were processed for JAK2V617F mutation analysis and cytogenetic studies, respectively. Genomic DNA was amplified by polymerase chain reaction, and fluorescent dye chemistry sequencing was performed by using the same primers that were used for amplification.RESULTSAmong 105 study patients, cytogenetic abnormalities were detected in 47 patients (45%), and the JAK2V617F mutation was detected in 52 patients (50%). Comparison of mutational frequencies between favorable (normal, sole 13q−, or 20q− clones; n = 70 patients) and unfavorable (all other abnormalities; n = 35 patients) cytogenetic categories revealed a significantly different incidence of homozygous JAK2V617F between them (9% vs. 23%, respectively; P = .04). Furthermore, the mutant allele coexisted with several recurrent cytogenetic lesions. Among 25 patients who received Epo either alone (n = 17 patients) or in combination with hydroxyurea (n = 8 patients), 4 patients (16%) achieved a response, and none of them were homozygous for JAK2V617F. Conversely, a response was more likely (P = .0001) in the presence of favorable cytogenetic abnormalities (i.e., 3 of 4 responders carried sole 13q− or 20q− clones).CONCLUSIONSUnfavorable and favorable cytogenetic clones in MMM clustered with homozygosity for JAK2V617F and treatment response to Epo‐based therapy, respectively. Cancer 2006. © 2006 American Cancer Society.

Oncogenic mechanisms in myeloproliferative disorders

“…Indeed, the vast majority (93-100%) of ET patients have low levels of mutated JAK2 and are described as 'heterozygous' for the mutation. In contrast, one third of PV and some IMF patients positive for V617F are described as 'homozygous', meaning that their granulocytes or bone marrow mononuclear cells harbour more mutated than wild-type JAK2 alleles [94,95]. As these analyses were performed with cell populations rather than by clonal assays, the frequency of mitotic recombination leading to homozygous subclones may have been underestimated.…”

Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European LeukemiaNet/MPN&MPNr-EuroNet (COST action BM0902) study

“…Mutant allele burden has been correlated with the risk of thrombotic events in ET, severity of the disease phenotype in PV and survival in PMF. 13, 14, 15, 16, 17, 18, 19, 20 JAK2 -V617F has also been quantified to assess disease response, with significant reductions in allele burden reported in PV patients following interferon α-2b and pegylated interferon α-2a treatment. 21, 22, 23, 24, 25 Moreover, serial DNA-based qPCR assays have been used after allogeneic transplantation for PMF to predict outcome, 26, 27, 28, 29, 30 with patients with an allele burden >1% on day 28 post-transplant 30 or failing to achieve molecular remission in the peripheral blood (PB) by 6 months post-allograft being at a significant risk of relapse, 29 which can potentially be prevented by donor lymphocyte infusion (DLI).…”

Advances in the Therapy of Chronic Idiopathic Myelofibrosis

“…, whereas the presence of favorable cytogenetic findings was associated with response to erythropoietin therapy [35].…”

“…In addition, the presence of unfavorable cytogenetic aberrancies appeared to be the strongest predictor of poor survival in patients with post-PV or post-ET myelofibrosis, which suggests that cytogenetic findings might supersede current prognostic systems in patients with secondary myelofibrosis [34]. In one study, cytogenetic abnormalities were detected in 47 (45%) of 105 patients studied, and the JAK2 V617F mutation was detected in 52 (50%) [35]. Unfavorable cytogenetic findings clustered with homozygosity for JAK2…”