The prognostic impact of germline 46/1 haplotype of Janus kinase 2 in cytogenetically normal acute myeloid leukemia

Abstract

The online version of this article has a Supplementary Appendix. BackgroundPrognostic risk stratification according to acquired or inherited genetic alterations has received increasing attention in acute myeloid leukemia in recent years. A germline Janus kinase 2 haplotype designated as the 46/1 haplotype has been reported to be associated with an inherited predisposition to myeloproliferative neoplasms, and also to acute myeloid leukemia with normal karyotype. The aim of this study was to assess the prognostic impact of the 46/1 haplotype on disease characteristics and treatment outcome in acute myeloid leukemia. Design and MethodsJanus kinase 2 rs12343867 single nucleotide polymorphism tagging the 46/1 haplotype was genotyped by LightCycler technology applying melting curve analysis with the hybridization probe detection format in 176 patients with acute myeloid leukemia under 60 years diagnosed consecutively and treated with curative intent. ResultsThe morphological subtype of acute myeloid leukemia with maturation was less frequent among 46/1 carriers than among non-carriers (5.6% versus 17.2%, P=0.018, cytogenetically normal subgroup: 4.3% versus 20.6%, P=0.031), while the morphological distribution shifted towards the myelomonocytoid form in 46/1 haplotype carriers (28.1% versus 14.9%, P=0.044, cytogenetically normal subgroup: 34.0% versus 11.8%, P=0.035). In cytogenetically normal cases of acute myeloid leukemia, the 46/1 carriers had a considerably lower remission rate (78.7% versus 94.1%, P=0.064) and more deaths in remission or in aplasia caused by infections (46.8% versus 23.5%, P=0.038), resulting in the 46/1 carriers having shorter disease-free survival and overall survival compared to the 46/1 non-carriers. In multivariate analysis, the 46/1 haplotype was an independent adverse prognostic factor for disease-free survival (P=0.024) and overall survival (P=0.024) in patients with a normal karyotype. Janus kinase 2 46/1 haplotype had no impact on prognosis in the subgroup with abnormal karyotype. ConclusionsJanus kinase 2 46/1 haplotype influences morphological distribution, increasing the predisposition towards an acute myelomonocytoid form. It may be a novel, independent unfavorable risk factor in acute myeloid leukemia with a normal karyotype.Key words: acute myeloid leukemia, prognosis, Janus kinase 2, 46/1 haplotype. Haematologica 2011;96(11):1613-1618. doi:10.3324/haematol.2011 This is an open-access paper. Citation: Nahajevszky S, Andrikovics H, Batai A, Adam E, BorsThe prognostic impact of germline 46/1 haplotype of Janus kinase 2 in cytogenetically normal acute myeloid leukemia

The germline JAK2 GGCC (46/1) haplotype and survival among 414 molecularly‐annotated patients with primary myelofibrosis

“…The lack of an association between leukemia‐free survival and the JAK2 46/1 haplotype further supports the notion that the adverse survival effect of nullizygosity for the JAK2 46/1 haplotype might be mediated by a predisposition to nongenetic causes of death. However, contrary to such suggestion, previous studies in patients with normal karyotype acute myeloid leukemia have instead implicated homozygous/heterozygous JAK2 46/1 haplotype as being associated with inferior survival, possibly related to increased risk of death from infection . In an elegant editorial that accompanied the latter study, Hermouet and Vilaine entertained the possibility that the JAK2 46/1 haplotype might be a marker of myelomonocytic dysfunction and might also provide fertile ground for the acquisition of additional mutations.…”

The JAK2 46/1 haplotype: a marker of inappropriate myelomonocytic response to cytokine stimulation, leading to increased risk of inflammation, myeloid neoplasm, and impaired defense against infection?

“…9 In the present issue of Haematologica, the same group found that the JAK2 46/1 haplotype is associated with an increased frequency of acute myelomonocytic leukemia and a tendency to reduced survival because of death from infection in patients with NK-AML. 10 The latter findings need confirmation by other studies, for it is of great interest to establish whether the JAK2 46/1 haplotype is in fact a marker of myelomonocytic dysfunction and subsequently an unfavorable risk factor in NK-AML, as Nahajevszky et al suggest, and/or in other disease categories. 10 In fact, although the majority of studies have failed to detect any association of the 46/1 haplotype with hematologic and clinical parameters (Table 1), Tefferi et al found that the 46/1 haplotype status influenced survival in primary myelofibrosis, and evolution toward myelofibrosis in polycythemia vera.…”

“…10 The latter findings need confirmation by other studies, for it is of great interest to establish whether the JAK2 46/1 haplotype is in fact a marker of myelomonocytic dysfunction and subsequently an unfavorable risk factor in NK-AML, as Nahajevszky et al suggest, and/or in other disease categories. 10 In fact, although the majority of studies have failed to detect any association of the 46/1 haplotype with hematologic and clinical parameters (Table 1), Tefferi et al found that the 46/1 haplotype status influenced survival in primary myelofibrosis, and evolution toward myelofibrosis in polycythemia vera. 5 Moreover, it has been reported that the frequency of the JAK2 46/1 haplotype is increased in the context of severe inflammation, for instance Crohn's disease.…”

Az akut myeloid leukaemia gyógyszeres kezelése. Jelenlegi lehetőségek, jövőbeli kilátások

“…Kedvező genetikai markerek (FLT3-ITD negatív, NPM/IDH mutáns betegek) esetén jobb, bizonyos mutációk (TET2, MLL-PTD, ASXLI, PHF-6) mellett rövidebb túlélés várható. Nahajevszky és mtsai [1] szerint a JAK2 (Janus kinase 2) 46/1 haplotípus szintén kedvezőtlen prognó-zist jelez normális citogenetikájú AML-es betegekben. A mutációs profil alapján a normális karyotypusú betegek kedvező, intermedier és kedvezőtlen prognózisú csoportba sorolhatók.…”