The <i>JAK2</i> 46/1 (<i>GGCC</i>) MPN‐predisposing haplotype: A risky haplotype, after all
Authors: Alessandro M. Vannucchi, Paola Guglielmelli
Journal: American Journal of Hematology (2018)

From being Cinderella among neoplastic diseases, owing to the disappointingly lack of knowledge about pathogenetic mechanisms and genetic basis long time after the seminal description by William Dameshek in 1951, the myeloproliferative neoplasms (MPNs) magically transformed into a charming princess after the identification of the JAK2V617F mutation in 2005.1 At the same time, this breakthrough discovery, and those that followed at accelerated pace thereafter, while providing evidence of involvement of additional somatically acquired mutations and concurrently facilitating the clinical development of the first in-class approved JAK1 and JAK2 inhibitor, made these apparently low-complexity diseases much more complicated than eventually anticipated. A likely yet too simplistic view of MPNs envisions complex interactions among individual characteristics (age, gender, hormones, others?), somatically acquired driver and non-driver mutations and additional cytogenetic abnormalities, an underlying inflammatory condition and other individual features, including germline characteristics (Figure 1A). In this scenario, familial clustering of MPNs has been long recognized; one large epidemiology study established that the relative risk of having an MPN in the family is increased by almost 6-fold in the presence of an affected relative.2 In 2009, three independent reports in Nature Genetics described a JAK2 haplotype, called GGCC or 46/1, located in the 3′-portion of the gene, that includes JAK2 and two other genes, insulin-like 6 (INSL6) and insulin-like 4 (INSL4) that are not normally transcribed in the hematopoietic system. The JAK2 46/1 (GGCC) haplotype can easily be addressed by analyzing four SNPs in complete linkage disequilibrium, located in introns 10, 12, 14, and 15 of the JAK2 gene3-5 (Figure 1B). This haplotype represents a low penetrance predisposition allele, found in about 50% of healthy subjects, and is associated with JAK2 mutated MPN6 and, according to some,7 but not all,8 reports also to JAK2 unmutated cases. In particular, according to recent data in 2035 MPN patients, of which 356 with a diagnosis of polycythemia vera (PV), who were extensively genotyped for a number of single nucleotide polymorphisms (SNPs) associated with hematologic traits and/or diseases, the JAK2 46/1 haplotype was found to strongly associate with diagnosis of PV (hazard ratio, 2.3). Additional genetic variations predisposing to MPN were later described in MECOM, TERT and HBS1L-MYB;9-11 the combined effect of JAK2/TER/MECOM variants was estimated to have a population association rate of 51% for JAK2-negative MPN.9 Genetic variants, like the JAK2 46/1 haplotype, might contribute to MPN pathobiology and disease' presentation, although the majority of studies failed to highlight meaningful associations of JAK2 46/1 haplotype with clinical and hematologic characteristics. In this issue of the Journal, Tefferi et al. report their findings on correlations of the JAK2 GGCC (46/1) haplotype with risk of any-cause death in primary myelofibrosis (PMF).12 The current series, that includes 414 patients, of which 69% presented the haplotype, extends and validates previous findings from the same research group in 130 cases, overall reinforcing the association of nullizygosity for the GGCC haplotype and inferior survival particularly in patients harboring the JAK2V617F allele. The current study provides also novel information regarding the interaction of the GGCC haplotype with other genetic features, including defined cytogenetic abnormalities and gene mutations whose prognostic relevance was established in the context of GIPSS13 and MIPSS70v2 score.14, 15 The findings that, in the context of the latter, the prognostic significance of the GGCC haplotype is lost due to its association with constitutional symptoms (which are not included in the GIPSS score) is intriguing, and deserves further investigation. One might hypothesize that the GGCC haplotype associates with, and contributes to, stronger downstream signaling from the constitutively activated JAK2V617F, which is involved in response and/or production of several inflammatory cytokines, or eventually contribute to higher cytokine production by bone marrow stromal cells possibly mediated by INSL6 and/or INSL4.16 Mechanistic involvement of JAK/STAT pathway in symptomatic burden that accompanies MPNs is supported by studies showing abnormal plasma cytokine profiles,17 themselves also of prognostic significiance,18, 19 as well as the remarkable anti-inflammatory properties of the JAK1 and JAK2 inhibitor ruxolitinib that favorably affects MPN-associated symptomatic burden.20, 21 These suggestions might be only apparently in conflict with findings in acute leukemia patients, showing the GGCC haplotype to be associated with an increased rate of deaths due to infections,22 possibly resulting from defective myelomonocytic function.16 Primary myelofibrosis is still an incurable disease for patients who are not successfully transplanted. However, owing to the still not negligible risk of mortality and relapse of the transplant procedure, appropriate selection of candidates with predicted best risk-benefit ratio is still an unmet clinical dilemma, both for the patients and the physicians; therefore, efforts to develop optimally performing risk scores for patients candidate to stem cell transplantation are fully justified in the aim of personalized medicine, and indeed are the focus of several recent studies. The most commonly used risk score is the IPSS and derivatives,23 based exclusively on clinical and hematological information, while the most recently developed MIPSS70/MIPSS70v2 and GIPSS are based largely or entirely on molecular (somatic mutations) and cytogenetic characteristics. The improved performance of the latter scores that incorporate disease-intrinsic molecular and cytogenetic information, especially in the most-difficult-to-counsel category of IPSS-intermediate risk patients, has been demonstrated. The significant association of nullizygosity for the JAK2 GGCC (46/1) haplotype with shortened survival in patients with PMF reported in current Tefferi's et al. study,12 that overpowers in terms of patients' numbers and proportion of primary event (death) two previous conflicting studies where no such association was reported, deserves renewed attention.24, 25 Owing that the JAK2 haplotype is preferentially associated with JAK2V617F mutated cases, the authors have also examined separately JAK2 mutated and wild-type patients, the latter divided according to their underlying driver mutation (MPL, CALR type1/like and CALR type2/like), and found the adverse survival effect being more pronounced in JAK2V617F mutated cases. One interesting hypothesis to test would be whether the prognostic significance of the GGCC haplotype is maintained, or is even more robust, in the setting of JAK2V617F mutated post-PV myelofibrosis, considering the enrichment of patients with loss of heterozygosity at the JAK2 locus in whom the impact of the JAK2 haplotype might be more evident. However, the ultimate question raised by the current study of Tefferi et al.12 is whether adding nullizygosity JAK2 46/1 haplotype to novel, genetic scores26 will contribute further to personalized prediction in PMF, a field where impressive improvements were made in the very few last years. Nothing to report.