Browsing by Autor "Javier Valencia"

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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.
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.
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.