Browsing by Autor "Silvia Mancilla"

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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.
Allogeneic Hematopoietic Progenitor Cell from Peripheral Whole Blood in Acute Myeloid Leukemia
(Elsevier BV, 2024) Ricardo Amaru; Reyna Mamani; Jeaneth Velarde; Mireya Carrasco; Edgar Teddy Quispe Soto; Silvia Mancilla; Juan Carlos Valencia; Daniela Patón; Ariel Amaru
Acute Myeloid Leukemia (AML) standard treatment involves initial induction therapy administrating two cycles of the 3+7 protocol (3 days anthracycline + 7 days cytarabine), and post-remission therapy of 3 cycles of high-dose cytarabine. The 5-year overall survival is 20 % (PMID: 33734442). During prolonged aplasia, infections and hemorrhages can cause treatment failure and death (PMID: 32236160). That is why transfusions of allogeneic hematopoietic progenitor cells (Allo-HPC) from whole peripheral blood to reduce the time of aplasia and complications were of interest. We studied 6 patients (3 males, 3 females) with AML (M1, M2), average age 35 years (18-60 years), who received Allo-HPC from whole peripheral blood during aplasia after each 3+7 regimen. The transfusion was performed at day 14 (day 12-16) post-regimen, when patients had neutrophils &lt;100/ul (0-100/ul). Regarding donors, one corresponded to HLA identical sibling, and 5 to haploidentical (2 fathers, 2 mothers and 1 brother), they received G-CSF 300 μg subcutaneously every 12 hours over 3 days, then 450 ml phlebotomy was performed. Phlebotomy displayed median WBC 27,310/ul, neutrophils 21,830/ul, CD34+ cells 9/ul, hemoglobin 14.8 g/dl, and platelets 218,000/ul. Thus, whole peripheral blood obtained was transfused through patients' CVC after premedication with dexamethasone 8 mg and metamizole 1 g. FISH (Y chromosome, Vysis CEP-Y DYZ1) and RT-PCR (HUMARA gene) studies were performed for chimerism analysis. Recovery of neutrophils &gt;500/ul was observed at day 9 and platelets &gt;20,000/ul at day 6. One case of cutaneous rush was observed as an adverse event. MRD after each cycle reflected 0.01% average. Three patients remain alive with follow-up of 4 years, 5 years and 1 year respectively. Two patients relapsed and died during 1year follow-up. One patient developed optic neuritis and did not receive high-dose cytarabine therapy, relapsed and died after 6 months. None of the patients presented acute or chronic GVHD. Regarding the results of chimerism, one male patient (1year follow-up) showed mixed chimera by FISH (Y=95%) and by RT-PCR (HUMARA gene), such studies were still in progress in the other two women patients. Contrasting patients who received Allo-HPC from the ones who do not, statistically differences were found in neutrophils recovery and hospital staying, the former displayed 9 + 3 days vs 14 + 4 days (p=0.008) and 19 +5 days vs 25 + 4 days (p=0.009) respectively, infections also decreased from 83% to 25%. Transfusion of Allogeneic Hematopoietic Progenitor Cell from Peripheral whole blood reduces the duration of aplasia, infections, inpatient stays, and increases survival.
Atorvastan, Apsirin and Hydorxyurea for an Effective and Low-Cost Treatment in High-Risk Polycythemia Vera
(European Medical Journal, 2022) Ricardo Amaru; Mireya Carrasco; Victor R. Gordeuk; Teddy Quispe; Silvia Mancilla; Daniela Patón; Ariel Amaru
Introduction: Polycythemia vera (PV) treatment focuses on preventing thrombotic events and delaying transformation to myelofibrosis or leukaemia. According to risk stratification, low-risk patients require therapeutic phlebotomy combined with acetylsalicylic acid, whilst the treatment of high-risk patients with PV relies on cytoreductive therapies, employing hydroxyurea (HU), ruxolitinib, or interferons. However, in low- and middle-income countries, the availability and cost of these drugs poses a challenge in treating high-risk patients, so optimising existing resources is required. Method: A prospective longitudinal study aimed to investigate the combination of atorvastatin (ATV), aspirin, and low-dose HU as a therapeutic strategy to treat PV in high-risk patients. The study evaluated the effect of statins on erythroid colony proliferation in vitro, as well as the applicability of ATV (20 mg/day), acetylsalicylic acid (100 mg/day), and hydroxiurea (500 mg/day) in high-risk patients with PV from La Paz, Bolivia, residing at 3,600 metres above sea level. Results: Simvastatin (3.5 μm) inhibited UKE-1 cell (JAK2V617F mutated) proliferation at 33%, and burstforming unit-erythroid colonies from patients with PV at 61%. Patients receiving ATV, aspirin, and low-dose HU displayed a good response and adequate tolerance to treatment (13-years follow-up). No patients experienced myelofibrosis or transformation to leukaemia, and no severe adverse events were observed. Conclusions: This accessible, effective, and low-cost therapeutic strategy could improve adherence to treatment and the overall survival of high-risk patients with PV in resource-limited countries.
Erythroid Leukemia Is Increased at High Altitude (4000 m)
(Elsevier BV, 2024) Ricardo Amaru; Maria Julieta Luna Leyza; Luis Felipe Mamani; Silvia Mancilla; Daniela Patón; Juan Carlos Valencia; Mireya Carrasco; Ariel Amaru
Acute erythroid leukemia (AEL) also known as pure erythroid leukemia (PEL) from the 2016 WHO update (PMID: 35264503; Wang, Am J Hematol. 2017; 92: 292-296) is a rare and unique subtype of acute myeloid leukemia (AML). It is characterized by immature erythroid precursors predominance with a high frequency of gains and amplifications involving EPOR/JAK2 (PMID: 35839275) and phosphorylation of ERK1/2 by inhibiting Fli-1 Promoter Activity (Min Mo, Catalysts, 2022. 13.1:84). AEL accounts for 1% of AML cases and can evolve from prior myelodysplastic syndrome or develop de novo, it is typically observed in adults with a median age ranging 66-68 years, and of dismal prognosis (&lt;6 months overall median survival) (PMID: 36323674). Its distinction attributes to erythroblastic proliferation (&gt;80%), pancytopenia, and extensive bone marrow involvement by proerythroblasts (≥30%). Common immunophenotype markers include CD105, CD34, CD71, CD36, CD235 (Wang, Am J Hematol. 2017). Moreover, it has been reported that hypoxia influences the development of erythroleukemia through various mechanisms, including promoting erythroid differentiation, inducing hemoglobin production, defining cell heterogeneity, regulating erythropoiesis, and influencing the bone marrow microenvironment (PMID: 33675821; 17255519). Regardingly, an overexpression of HIFs is related with a bad prognosis in AML (PMID: 25687039), HIF-1α is involved in cancer early stages, whereas HIF-2α in the later stages (PMID: 29753878). HIF-2a expression plays an important role in regulating proliferation in erythroleukemia cells under hypoxia (PMID: 26898802). Thus, we aimed to search for the hematologic and immunophenotypic characteristics of AEL cases among all AML diagnoses at high altitude. We retrospectively analyzed cases of AML diagnosed in Bolivia from the period of May 2019 to April 2024 considering the different altitudes 4000m (n=68), 2000m (n=62), and 400m (n=71), and gathered a comprehensive account of hematologic, bone marrow morphology, and immunophenotypic features. Among AML cases (n=201), 13 cases of AEL were identified which corresponded to 6.5 %. Interestingly, AEL cases at 4000 m accounted for 13.2 % (female 2, male 7, median age 54 years), and this was significantly higher (p=0.02) when compared to cases at 2000 m representing 3.2 % (female 1, male 1, median age 75 years) or at 400 m with 2.8 % (female 2, median age 52 years). Hematologic indices displayed mean Hb 7.3 g/dl, WBC: 11515/ul and Plt: 127154/ul. Bone marrow findings reflected &gt; 80% of prominent erythroid precursors with large irregular nuclei, dispersed chromatin, 1 to 3 elongated nucleoli, deeply basophilic cytoplasm, and an intense mitotic activity. Immunophenotypic features revealed CD34, CD71, CD105, CD36 and CD235 regarding erythroid clonality. AEL incidence is increased at high altitude, reflects intriguingly morphology and hematological characteristics. This increase may be due to the increase in HIF and Epo at high altitude, since the barometric pressure (462 mmHg) and the oxygen level in the air (14%) at high altitude are low. So, further studies elucidating the genetic mechanism involved are of interest.
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.