Browsing by Autor "Julieta Luna"

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Acute promyelocytic leukemia incidence in Andean highlanders with the NFKB1 haplotype (rs230511)
(Elsevier BV, 2025) Ricardo Amaru; Victor R. Gordeuk; Julieta Luna; Edgar Teddy Quispe Soto; Silvia Mancilla; Javier Valencia; Luis Felipe Mamani; Daniela Patón; Ariel Amaru
Abstract Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML), characterized by the oncogenic fusion protein PML-RARα, which results from the t(15;17) chromosomal translocation. APL accounts for approximately 4-10% of AML cases worldwide. The median age at diagnosis falls around the fifth decade of life, with a slight male predominance (PMID: 39682277). The PML-RARα fusion protein plays an essential role in the pathogenesis of APL by enhancing hypoxia-inducible factor (HIF)-driven transcriptional activity. PML-RARα acts as a transcriptional co-activator of HIF-α, amplifying HIF-mediated transcription independently of PML protein inhibition. This activation is unique to APL-specific fusion proteins; it is absent in other AML subtypes. The interaction of PML-RARα and HIF factors significantly influences disease progression and relapse. (PMID: 24711541). Transcriptomic analyses of APL cells reveal enrichment of NF-κB signaling pathways among differentially expressed genes, particularly those involved in cancer pathways. This suggests that NFKB1 contributes to the proliferative and survival signaling in APL cells (Villiers W, Nat. Commun, 2023). However, PML-RARα disrupts NF-κB activity by inhibiting phosphorylation and DNA binding of the NF-κB p65 subunit, suppressing NF-κB target gene expression. This disruption contributes to leukemogenesis through impaired differentiation and altered transcriptional regulation (Ahmed A, Sci.rep, March 2017). The incidence of APL varies across geographic regions and ethnic groups. Higher frequencies have been observed in Latin American populations compared to North America and Europe. These disparities suggest that genetic and environmental factors contribute to differences in disease distribution and outcomes (PMID: 12935956) and currently, there are no published data directly comparing APL incidence between populations living at sea level and those residing at high altitudes. We investigated the proportion of AML cases diagnosed as APL in Bolivian Andean highlanders residing at 4000 m, a population characterized by elevated HIF-α expression and a predominant NFKB1 haplotype rs230511 (95%) that results in a non-functional NFKB1 protein. We then compared the proportion of APL cases from Bolivian populations living at 2000m and 400 m. We analyzed 1,273 AML diagnoses from January 2000 to June 2025, grouped by altitude of residence: 406 at 4,000 m (mean age 37 years), 412 at 2,000 m (mean age 41 years), and 455 at 400 m (mean age 28 years). The overall mean age at AML diagnosis was 35 ± 25 years, with a male predominance of 54%. Among the total AML cases, 140 (11.0%) were identified as APL. We compared the proportion of AML cases classified as APL across three altitudes: at 4,000 m, 38 of 406 AML cases (9.4%) were APL; at 2,000 m, 46 of 412 cases (11.2%); and at 400 m, 56 of 455 cases (12.3%). There was a trend toward a lower proportion of APL cases at 4,000 m compared to 2,000 m and 400 m, although this difference was not statistically significant (P = 0.17). The age distribution of APL cases was as follows: 1-17 years, 44 cases (31.4%); 18-39 years, 59 cases (41.7%); 40–59 years, 30 cases (21.4%); and ≥60 years, 7 cases (5.0%). The age of AML patients was significantly lower at 400 m compared to the higher altitudes, whereas the proportion of males did not differ significantly by altitude. ConclusionsThe APL tends to decrease with increasing altitude, consistent with genetic adaptations in high-altitude Andean populations (~4000 m) involving increased HIF activity and a specific NFKB1 haplotypeThe 25-year incidence of APL was significantly lower in the La Paz population at 4000 m compared to populations at lower elevations (P &lt; 0.020).Individuals younger than 40 years are disproportionately affected, representing 73.1% of APL cases. The increased incidence in younger age groups does not vary by altitude, suggesting that genetic factors may predominantly drive this demographic pattern.Investigating genetic adaptations in high-altitude populations could offer novel insights into APL pathobiology and therapeutic strategies.
ALTAS DOSIS DE COBALAMINA Y ÁCIDO FÓLICO EN EL TRATAMIENTO DE LEUCOPENIAS POST COVID-19
(2021) Ricardo Amaru; Mireya Carrasco; Jeaneth Velarde; Reyna Mamani; Daniela Patón; Julieta Luna
Andean Aymara Enriched Genetic Variants Are Beneficial to High Altitude Adaptation of Andean Quechuas Living at 5000 m
(Elsevier BV, 2022) Ricardo Amaru; Emerson Cayo; Julieta Luna; Teddy Quispe; Josef T. Prchal; Jihyun Song
Populations living at high altitude developed distinct evolutionary genetic adaptations allowing them to exist in extreme hypobaric hypoxia condition. Tibetans and Andean highlanders (Aymaras and Quechuas) have inhabited regions over ~4000 m for 44,000 and 14,000 years, respectively (PMID: 28448578, 25342802). Unlike other high-altitude populations, such as Tibetans, Andeans' Aymaras and Quechuas have higher hemoglobin levels. Tibetan genomic analyses revealed evolutionary selected genetic signatures EPAS1, EGLN1 and PKLR genes (PMID:25129147; Song, ASH 2018). However non-DenisovanEPAS1 variants (rs13005507 and rs142764723) are present in Aymaras and Quechuas, and ~56% of Aymaras have Tibetan PKLR variants (Song, ASH 2018). Our whole genome study found that most Aymara evolutionary-enriched genes (BRNIP3, NOS2, SH2B1, and TBX5) are associated with cardiopulmonary development but not with hemoglobin levels (PMID: 29100088); different genomic selection was reported in Andean Quechuas (PMID:23954164). We then found previously unreported Aymara enriched NFKB1 single nucleotide polymorphisms (SNP) by integrative analysis of the Aymaras' genome and transcriptome, this SNP is also enriched in Quechuas but to the lesser degree. Decreased NFKB1 results in increased NF-kB levels leading to NF-kB driven increased inflammation as well as increased HIFs activity (PMID: 26513405) and is associated with high hemoglobin and inflammatory protein and transcript levels in Aymaras (Song, ASH 2018). We studied the presence of Aymara enriched SNPs in Quechua, one of Andean population living in Chorolque (5000 m) and their association with phenotypes at high altitude. We genotyped 5 Aymara enriched SNPs and PKLR (Table) in Quechuas (45 men, 14 women) living in Chorolque (5000 m) mining district, Potosi-Bolivia. All men were smokers while none of women were smokers. We also measured laboratory phenotypes leukocytes, platelets, lymphocytes, monocytes, neutrophils, as well as hemoglobin dissociation p50, SpO2, lactose, hemoglobin and hematocrit to study if genetic variants play a role in changes in these phenotypes. All Aymara enriched allele frequencies in Quechuas were lower than in Aymaras (Table). The allele frequencies of BRINP3, SH2B1, TBX5 in Quechuas were significantly different from those in Aymara, suggesting that Quechuas share some but not all genetic background with Aymaras. Since all men were smokers, we tested smoking effect on these phenotypes. Except hemoglobin and hematocrit levels, other phenotypes were comparable to women without smoking history. BRINP3 SNP positively correlated with SpO2 levels (r=0.2252, p=0.0893), suggesting that this SNP may have a role in delivery oxygen to tissue. PKLR SNP is associated with decreased levels of pyruvate kinase transcript levels, leading to increase 2,3 DPG and shifting hemoglobin dissociation curve to the right (increase of p50) (Song, ASH 2018). However, in these subjects, we did not find association in p50 but positive correlation with SpO2 (r=0.3423, p=0.0082). It suggests that presence of BRINP3 and PKLR SNPs is beneficial to live at low oxygen tension by delivering more oxygen to tissues. Total leukocytes, lymphocytes, and neutrophils were negatively correlated with NFKB1 SNP (r=-0.2349, r=-0.281, and r=-0.1725, respectively) which differed from our previous study of Aymaras at La Paz, suggesting that Quechuas may have different mechanisms in responding to inflammation from Aymaras. None of SNPs were associated with hematocrit and hemoglobin levels in men; however, we could not exclude effect of smoking. In females, NOS2 SNP were positively correlated with both hemoglobin and hematocrit (r=0.5513, p=0.0246). NO (nitric oxide) synthesized by NOS2 inhibits erythropoiesis (PMID: 18282521), suggesting that NOS2 SNP may decrease NO production resulting in inducing erythropoiesis in Quechuas. We conclude that while Quechuas and Aymaras share some genetic variants, but they differ in degree of selection for these SNPs. BRINP3 and PKLR SNPs are helpful to transfer more oxygen to tissues at high altitude. NFKB1 SNPs` inverse correlation with immune cells may provide protective functions in response to increased inflammation at high altitude (PMID: 26855492). Decreased NO production by NOS2 SNP may augment erythropoiesis in Quechuas, resulting in their higher hemoglobin and hematocrit at high altitude compared to Europeans. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal
Andean high-altitude dwellers with the NFKB1 haplotype (rs230511) are protected from acute mountain sickness
(Elsevier BV, 2025) Ricardo Amaru; Javier Valencia; Edgar Teddy Quispe Soto; Emerson Cayo; Julieta Luna; Daniela Patón; Victor R. Gordeuk; Josef T. Prchal; Jihyun Song
Abstract Acute Mountain Sickness (AMS) occurs with rapid ascent to high altitudes (&gt;2,500m), where air and oxygen pressures are lower than at sea level. AMS symptoms are headache, loss of appetite, nausea, dizziness, insomnia, fatigue and chest tightness, but severe AMS can progress to cerebral edema or pulmonary edema (PMID:26294748). Hypoxia at high altitude activates inflammatory pathways in which NF-κB signaling plays a central role. Severe hypoxia (1–3% O2) induces NF-κB-driven production of inflammatory mediators, connecting hypoxia-induced stress mediated by hypoxia-inducible factors (HIFs) with NF-κB. HIFs are also involved in responses that increase pulmonary vascular permeability, pulmonary hypertension, and edema (PMIDs:11441701;3410239;18641050). HIFs increase blood-brain barrier permeability, a central feature of high-altitude cerebral edema (PMID:33856254). NFKB1 is part of NF-κB complex and modulates NF-κB activity. NFKB1 also augments activity of HIFs. In our study of evolutionary adaptation to extreme high altitude of Andean native Aymara who have higher hemoglobin than Europeans living at the same high-altitude (PMIDs: 24039843; 29100088), we reported that the evolutionary selected T allele of NFKB1 rs230511 haplotype is linked to previously unreported alternate splicing of NFKB1, including skipping exon 4, exon 5, or both exons 4 and 5. It is present in ~90% of Aymara, but it also exists at lower frequency in Europeans, Asians and Hispanics (~30%). These alternatively spliced NFKB1 transcripts result in partial or complete loss of NFKB1 protein expression. This Aymara NFKB1haplotype is associated with increased baseline expression of inflammatory and HIF-regulated genes and correlates with those Aymara having high hemoglobin. However, under inflammatory stress, it has the opposite effect: nuclear translocation of NF-kB protein is attenuated, resulting in reduced expression of inflammatory, HIF-regulated, and prothrombotic genes (PMID:39971917). Since the incidence of AMS in the Aymara population is 0.6 % (Viruez, Horiz Med [Lima] 2020; 20(3): e943), which is markedly lower than the 1.7 % observed in non-Aymara at the same altitude (Castellanos, Correo Científico Médico 2022; 26), we hypothesized that rs230511-T is also associated with a protective role for AMS in Aymara. We studied 35 Bolivian Aymara in LaPaz (altitude of 4000 meters) who relocated to lower altitudes (&lt;400 m) for 1 month to 5 years and then returned to 4000 m and developed AMS. Among 35 subjects, 10 participants- 5 women (age 29±14 years) and 5 men (age 39±8 years)- without a history of medical comorbidities (except for one having history of gout) developed AMS. The 25 subjects who did not develop AMS served as controls (7 women, age 40±14 years and 18 men, age 38±11 years). All participants were genotyped for the NFKB1(rs230511) and NOS2 (rs34913965) variants; NOS2 was included due to a potential relationship with AMS (PMID:29100088). Among the subjects who developed AMS, the allele frequencies for the Aymara-enrichedNFKB1 variant were C:0.75 and T:0.25, compared to C:0.0 and T:1.0 in the control group (p&lt;0.0001). The genotype frequencies were CC:50%, CT:50% and TT:0% in the AMS group and CC:0%, CT:0% and TT:100% in the control group (p&lt;0.0001). For the NOS2 C/T haplotype variant, analysis of 7 AMS patients revealed that allele frequencies (T-Aymara enriched allele PMID:29100088) were C:0.14 and T:0.86, compared to C:0.1 and T:0.9 in the control group (p=0.5146). The genotype frequencies were CC:0%, CT:29%, and TT:71% in the AMS group, but CC:4%, CT:12%, and TT:84% in the control group (p=0.011). We classified AMS severity as severe (4 patients admitted to the intensive care unit), moderate (2 patients hospitalized), and mild (4 patients managed at home). Two patients with severe AMS who developed both pulmonary and cerebral edema had an Aymara NFKB1 allele frequency of C: 1.0 and T: 0.0, a 100% CC genotype. Our findings suggest that the presence of the Aymara evolutionary selected NFKB1 haplotype protects from developing AMS, whereas its absence (CC genotype) increases the likelihood of development of severe AMS. The CT genotype of NOS2 variant may also provide some protective effect. Larger cohorts and functional assays are needed to validate these associations and to further explore the molecular mechanisms by which the NFKB1 and NOS2 variants contribute to protection against AMS.
History of Thrombosis at High Altitude Associates With Increased Erythropoietin
(Wiley, 2025) Ricardo Amaru; Josef T. Prchal; Mireya Carrasco; Silvia Mancilla; Teddy Quispe; Julieta Luna; Juan Carlos Valencia; Daniela Patón; Victor R. Gordeuk
In Bolivian Aymara with erythrocytosis, elevated erythropoietin strongly associates with history of thrombosis. Hypoxia and iron deficiency predict elevated erythropoietin, but they do not have a direct relationship with thrombosis history. Source: Artwork by Nadia Gordeuk.
Low incidence of HTLV-1 infection in Andean highlanders with NFKB1 haplotype
(Elsevier BV, 2025) Silvia Mancilla; Luis Malpica; Javier Valencia; Julieta Luna; Rodolfo Urquidi; Alex Chaman; Daniel E. Martínez; Jeaneth Velarde; Ricardo Amaru
Abstract Human T-cell lymphotropic virus type I (HTLV-1) is a retrovirus infecting T-lymphocytes recognized as the causative agent of adult T-cell leukemia/lymphoma (ATL). Approximately 5 % of individuals infected with this virus develop ATL after a prolonged latency period, often several decades (PMID: 36800643). The genome of HTLV-1 involves the regulatory protein Tax which plays a central role in the survival, proliferation, and transformation of HTLV-1-infected cells into malignant cells. By constitutively activating the IKK complex, Tax-1 oncoprotein induces persistent NF-κB activation that drives the proliferation and survival of infected T-cells, thereby contributing to leukemogenesis in ATL (PMID: 29685460). Persistent activation of NF-kB induces canonical and noncanonical pathways that entail a key role for host cell transformation, hence its importance as a target in therapeutics (PMID: 20845110). Reports display that canonical NF-κB activation by Tax would likely be disrupted, impairing key oncogenic mechanisms of HTLV-1 (PMID: 29515558; PMID: 29722927). Concerning NF-κB, it has been reported of a NFKB1 rs230511 haplotype enriched in the Andean population, which entailing an alternative splicing that skips exons 4 and 5 involves a loss of function affecting the functional levels of NFKB1, and inflammatory-related genes (PMID: 39971917). Andean region is known to be endemic for HTLV-1 (PMID: 23162541), therefore in order to elucidate the incidence of HTLV-1 in Andean with NFKB1 haplotype, we performed a screening to normal blood donors and hematologic diseases patients. A total of 462 blood samples were collected from individuals living in the Bolivian Andean region at 4000 meters above sea level where NFKB1 rs230511 haplotype prevalence stand for 95 %, and genotypic frequency corresponds CC 5 %, CT 33%, TT 62% and the allele frequency reflects T=0,88, C=0,12. (Blood, ASH 2316,2018; Hematol Mex 2023; 24(2):52-67). Among the samples, 247 were from normal blood donors (152 females with an average age of 24 years and 95 males with an average age of 32 years), the remaining 215 samples came from patients with hematologic diseases (109 females with average age 51 years and 106 males with average age 53 years). Of these patients, 46 were diagnosed with chronic myeloid leukemia (CML), while 169 had other non-malignant hematologic conditions. All specimens were screened using both the ASSURE HTLV-I/II Rapid Test and HTLV-I/II ELISA 4.0 (MP Biomedicals Asia Pacific). Any reactive samples were subsequently confirmed with a supplementary western blot assay (HTLV BLOT 2.4, MP Biomedicals Asia Pacific). Interestingly, out of 462 specimens, only one tested positive for HTLV-1 (0,22 %). This positive case corresponded to a patient with a hematologic disease who had received massive blood transfusions (&gt;20 units). Results display an extremely low HTLV-1 Incidence in Bolivian Andean region compared to other ethnic groups where prevalence exceeds 10%. This low incidence may be related to the fact that approximately 95% of the Andean population carries a nonfunctional NFKB1 haplotype, potentially limiting HTLV-1 pathogenesis. Further studies focusing anti-HTLV-1 antibody responses in individuals with NFKB1 deletion are needed to understand the molecular mechanism concerned.
Mayor prevalencia de leucemia eritroide aguda en residentes de gran altitud (4000 m)
(2025) Ricardo Amaru; LF Mamani; Julieta Luna; Teddy Quispe; Javier Valencia; Mireya Carrasco; Daniela Patón; Silvia Mancilla; Aléxia Rodriguez Amaru
Introducción: La leucemia eritroide aguda (LEA) es un subtipo raro y agresivo de leucemia mieloide aguda, asociada a mutaciones bialélicas del gen TP53. La edad media de diagnóstico es 67 años conllevando una proporción hombre:mujer de 2,4:1. La hipoxia y los factores inducibles por hipoxia (HIF) parecen desempeñar un rol en el desarrollo de LEA mediante mecanismos que involucran la diferenciación eritroide, producción de hemoglobina, regulación de eritropoyesis y modificación del microambiente de la médula ósea. Por lo que, para discernir sobre la influencia de la hipoxia en este subtipo de leucemia, es de interés analizar su prevalencia y características en poblaciones residentes a gran altitud. Material y Métodos. Estudio retrospectivo que consideró casos de LMA (n=211) diagnosticados en Bolivia durante el periodo de mayo de 2019 a octubre de 2024, se identificó casos del subtipo LEA (n=15) y se recopiló datos demográficos, hematológicos, morfológicos e inmunofenotípicos. El análisis estadístico contempló categorizar los casos de LMA y subsecuentemente de LEA según la altitud de presentación: 4000m, 2000m y 400m. Resultados. Los casos de LEA en Bolivia correspondieron al 7,5 % entre todos los casos de LMA, la edad media de presentación fue 53 años con predominio en varones (1,5:1). Distribuidos por altitudes, los casos de LEA a 4000 m (n=10) representaron el 14,1 %, significativamente mayor (p=0,01) comparado con el 4,5 % observado en los casos a 2000 m (n=3) y 2,7 % en los casos a 400 m (n=2). Los índices hematológicos de LEA reflejaron hemoglobina media de 7,3 g/dl, leucocitos 10266/ul y plaquetas 82267/ul, sin diferencias epresentativas entre las diferentes altitudes. Los rasgos de médula ósea reflejaron >80% de precursores eritroides prominentes con núcleos grandes e irregulares, cromatina dispersa, 1 a 3 nucléolos alargados, citoplasma profundamente basófilo e intensa actividad mitótica. Las características inmunofenotípicas mostraron clonalidad eritroide 90 % (CD34, CD71, CD105, CD36, CD235) y clonalidad mieloide 1,4 % (CD117, CD34). Conclusiones. El porcentaje de LEA (14,1 %), respecto del total de casos de LMA, está aumentada en la altitud (4000 m). Tal aumento podría deberse al incremento de HIF y Eritropoyetina en ambientes de hipoxia hipobárica.
Phenotypic Variations Related to Hypoxic Responses Among Andean Highlanders Living at Different Altitudes (400m, 4000m, 5000m)
(Elsevier BV, 2022) Ricardo Amaru; Emerson Cayo; Teddy Quispe; Juan Carlos Valencia; Daniela Patón; Luis Felipe Mamani; Julieta Luna
Introduction Adaptation to high altitude poses selective evolutionary changes involving multiple and challenging adaptive responses, and one of them deals with the low pressure of oxygen. Native Bolivian Andeans have lived at an average of 3000-5000 m for about 14,000 years, and have developed different erythroid phenotypes compared to other populations living at high altitude (PMID 30781443; PMID 25342802). Although Andeans have developed genetic adaptations related to erythropoiesis regulation (Blood, ASH 2316, 2018) they still undergone with polycythemic states, and those of clinical relevance are often Chronic Mountain Sickness erythrocytosis (CMS-E), secondary erythrocytosis (SE) and polycythemia vera (PV) (Rev Hematol Mex. 2016 Jan;17(1):8-20). Either adaptation or erythrocytosis condition entails important changes in hemoglobin, SpO2, P50 and lactate, so evaluating significant changes among Andeans living at different altitudes as well as the modifications between erythrocytosis patients and healthy highlanders became of interest. Material and method We collected venous blood samples from Bolivian native Andeans born at 4000 m (n=124) but living at 3 different altitudes (400 m, 4000 m, 5000 m), aside from Europeans (n=11) residing at 4000 m. Complete blood count, venous blood gas, and oxygen saturation studies were performed. P50 was measured by using a formula described by Lichtman. Likewise, a differential diagnosis regarding healthy inhabitants and polycythemia patients was performed. Results In healthy Andean inhabitants in different altitudes, the Hb levels increased at increasing altitude (p:0.001), meanwhile SpO2 (p:0.001) and P50 (p:0.001) decreased. No lactate variations among them were observed (Table 1). European subjects at 4000 m in relation to Andean inhabitants at the same altitude displayed higher Hb levels (p: 0.01), without variations in SpO2 and P50, but a significant increased lactate (p: 0.001) (Table 1). When comparing healthy subjects and patients with erythrocytosis (CMS-E, SE, PV) at 4000 m, the latter displayed higher Hb levels (p:0.001), decreased SpO2 (p:0.001), no variations in P50, and increased lactate in CMS-E and SE patients (p:0.01) (Table 2). Similarly, patients with erythrocytosis (CMS-E, SE) at 5000 m, related to healthy subjects at the same altitude, reflected increased Hb (p:0.001), decreased SpO2 (p:0.01), P50 without variations, and increased lactate (p:0.01) (Table 2). Conclusions Native Andeans from Bolivia born at 4000 m but living at different altitudes have variations regarding hematological phenotypes, decreased P50 shifts the hemoglobin dissociation curve to left. Patients with erythrocytosis have distinct phenotypes in relation to healthy subjects characterized by decreased saturation and increased lactate. Higher Hb levels and increased lactate in Europeans living at 4000 m probably due to the different residing time at high altitude, since native Andean inhabited high-altitude regions for many years. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal
VALORES DE HEMOGLOBINA EN LA POBLACIÓN DE CHOROLQUE A 5000 MSNM
(2020) Emerson Cayo; Ricardo Amaru; Daniela Patón; Teddy Quispe; Silvia Mansilla; Julieta Luna