Exploring hematological alterations and genetics associated with SNV rs10974944 in myeloproliferative neoplasms in Amazonian patients – Scientific Reports

Myeloproliferative neoplasms have characteristic changes on laboratory examination, as well as genetic findings that allow their recognition and differentiation. The discovery of genetic alterations involving introns is not yet fully understood, but is of growing interest in understanding causative factors and the role of these DNA regions in these diseases.

Essential thrombocythemia was shown to be the most common myeloproliferative neoplasm, findings consistent with the premise established by Torres¹⁵who studied a population BCR::ABL1– Negative myeloproliferative neoplasms in Amazonas (Brazil). Macedo describes similar data¹⁶they reported a similar situation in patients with the same hematological malignancies from the states of Paran and São Paulo, and these data are consistent with descriptions found in other countries^17,18.

The age range of the individuals was between five and seven years old, which is consistent with what has been described in other studies^{19,20 points}.Gradual accumulation of genetic variation in hematopoietic stem cells and biological mechanisms of DNA repair systems^21,22an increase or decrease in telomeres^23,24 and cumulative lifetime exposure to risk factors, such as smoking and obesity^25,26may explain the prevalence of this age group in the context of myeloproliferative neoplasms.

In terms of clinical features, polycythemia vera (PV) affects an equal proportion of men and women, while cases of essential thrombocythemia (ET) are predominantly female, and these data are consistent with the literature^27,28.Some studies suggest women are at increased risk of myeloproliferative neoplasms²⁹ Higher likelihood of developing cardiovascular complications and splenomegaly²⁶.The cause of this risk is unknown, but changes in sex chromosomes, hormonal factors, and gene expression may be contributing factors to this process²⁸.Laboratory data and thrombotic and hemorrhagic events for each tumor were presented as expected: PV showed a higher incidence of increased erythrocytogram values, ET showed changes in the megakaryocyte series and a higher risk of hemorrhagic events, as described by the World Health Organization³and other research on the topic^27,30.

Regarding genetic findings, PV showed a higher prevalence of positive cases JAK2 V617F variant because it is directly related to the specific pathogenesis of this hematological malignancy³⁶ and plays a role in constitutive activation of the JAK-STAT pathway⁵.Interestingly, 58% of our PV population was positive for this variant, which may initially differ from findings commonly described in the literature, which indicate JAK2 V617F The frequency of Brazilian, Korean, Chinese, Japanese and European patients exceeds 70%^{31,32,33,34,35}.

Compared with data documented in the literature, our analysis revealed significant specificity in our population, particularly among patients with PV, in whom 42% did not develop JAK2 V617F Variants or other pathogenic genetic changes along coding regions Jak 2according to the diagnostic criteria of the World Health Organization³. This atypical behavior indicates a major gap in our understanding of the genetic factors underlying the pathogenesis of myeloproliferative neoplasms in Amazonian populations. This gap highlights the urgent need for further research to more fully understand the genetic signatures and other contributing factors to these diseases.Therefore, it is recommended to conduct more studies in our population exploring other genes related to myelopoiesis and epigenetic regulation, e.g. DNMT3A (DNA Methyltransferase 3 Alpha), NFE2 (nuclear factor erythrocyte 2), SF3B1 (splicing factor 3b subunit 1), TET2 (Tet methylcytosine dioxygenase 2), ASXL1 (ASXL transcriptional regulator 1) and EZH2 (Zeste 2 Enhancer of polycomb repressive complex 2 subunit)^21,52. Analysis of these genes may provide valuable insights into the genetic behavior of myeloproliferative neoplasms in Amazonian populations and elucidate other factors involved in PV pathophysiology, in addition to known variants. JAK2 V617F and Jak 2 Exons 12 and 14.

In the literature, germline haplotype 46/1, represented by rs10974944 (C>G) variant, with JAK2 V617F^14,36,37,38 As observed in our study.Data on minor allele frequencies rs10974944 Brazil and the Amazon are still sparsely populated, making this study groundbreaking in its investigation. The lack of previous studies of this variation in Amazonian populations highlights the importance of the current work in filling gaps in genetic knowledge of this population.However, the frequency of the 46/1 haplotype is similar to rs10974944associated with a higher prevalence in patients with myeloproliferative neoplasms, especially those with myeloproliferative neoplasms JAK2 V617F⁺. This association was not only observed in other Brazilian populations, as described by Macedo et al.¹⁶ As discussed in one of our previous comprehensive reviews, studies have also been conducted on different populations around the world, including Asian, European, and North American populations¹³. Furthermore, the ancestral contribution to the Brazilian population, especially in the Amazon region, is characterized by a mixture of three main ethnic groups: Native Americans (NAM), Europeans (EUR) and Africans (AFR)³⁹. Therefore, it is reasonable to infer that the genetic behavior of variants in these populations is similar, as discussed previously, thereby strengthening the discussion about similar behavior in our populations.

High frequency of G allele rs10974944 positive in individuals JAK2 V617F Helps discuss non-random correlations between these two genetic alterations^13,40 This relationship is consistent with another finding of our study, that haplotype 2 (rs10974944G/rs10815151C/rs1011004A/rs77375493T), which reinforces the concept based on the interaction between rs10974944 (C>G) and JAK2 V617F (rs77375493G>T).These assertions are consistent with findings involving haplotype 46/1 in other Brazilian, Taiwanese, European, Chinese and Japanese populations.^{16,32,33,34,41}showing possible mechanisms prior to acquisition JAK2 V617F Not restricted to a specific race; therefore, its evolutionary basis can be considered a genetic susceptibility factor to the disease⁸.

Research report shows individuals with the GG genotype are at higher risk rs10974944 Actively JAK2 V617F^14,40,42.Consistent with the findings above, our group had a four-fold increased risk of positive JAK2 V617F In individuals with the GG genotype rs10974944 (OR 4.1; 95% CI 813.9).These findings support the hypermutability hypothesis, which establishes haplotype 46/1 as Jak 2 genes, which increases the risk of DNA replication errors and provides mutagenic conditions for obtaining variants with a selective advantage, e.g. JAK2 V617F^43,44,45.

the association’s rs10974944 (G) and JAK2 V617F VAF showed that haplotype 46/1 may be involved in clonal expansion.We found that individuals carrying the G allele had a six-fold higher risk rs10974944 and JAK2 V617F VAF is 50%.Our data suggest that markers of haplotype 46/1 may not only be acquired JAK2 V617F but also due to clonal expansion, maintenance and survival.Teferi⁴⁶ suggestion JAK2 V617F is not the initial clonogenic event in MPN, but one of several subclones derived from an ancestral clone. This is consistent with the annotation of Pardanani et al.⁴⁷which supports the hypothesis that this haplotype is located in a favorable cis-regulatory environment that facilitates the acquisition of JAK2 V617Fwhich in turn is responsible for clonal expansion and MPN development.

Furthermore, the possible role of acquired uniparental disomy, a genetic event leading to mitotic recombination, is associated with a neutral loss of heterozygosity on chromosome 9p in MPN patients, thereby reducing the haplotype and JAK2 V617F to homozygous state^14,48,49,can not rule out.In this case, it is theoretically possible that cells with both mutations would have a selective advantage, which would favor greater myeloproliferative potential and the establishment of mutant cells over healthy cells, thus explaining why in individuals with the combination Increase in VAF rs10974944 (G)+rs77375493 (T)(JAK2 V617F) homozygosity.

Associations between changes in hematological parameters, clinical features and the presence of 46/1 have been observed in the literature^16,33,50; However, this is not the scientific consensus⁸. Our data showed significant differences in MCV, MCH values ​​in the PV group as well as RBC, Hb, and Ht in TE carriers of the G allele. rs10974944which has been observed in previous studies^7,42,51.major demonstration rs10974944 Thrombotic events reinforce the use of this variant as a tool to monitor patients and investigate the clinical manifestations of polycythemia vera. To determine this association more reliably, new studies in more robust populations are needed to observe the behavior of this variant in relation to clinical and hematological features in patients with polycythemia vera.

This study uses the 46/1 haplotype for the first time. rs10974944 Variant, present in intron 12 Jak 2, a population from the Brazilian Amazon.The results of this study show that the rs10974944(G) variant is associated with JAK2 V617F⁺ variants, especially in PV_JAK2 V617F⁺ patient.Association of this variant with high allelic variant burden JAK2 V617F, thrombotic events and hematological changes were also observed. This variant is promising for clinical use in investigating and monitoring laboratory changes and/or increases in VAF in identified hematological malignancies.