RESUMEN
MicroRNAs and heterogeneous ribonucleoproteins (hnRNPs) are posttranscriptional gene regulators that bind mRNA in a sequence-specific manner. Here, we report that loss of miR-328 occurs in blast crisis chronic myelogenous leukemia (CML-BC) in a BCR/ABL dose- and kinase-dependent manner through the MAPK-hnRNP E2 pathway. Restoration of miR-328 expression rescues differentiation and impairs survival of leukemic blasts by simultaneously interacting with the translational regulator poly(rC)-binding protein hnRNP E2 and with the mRNA encoding the survival factor PIM1, respectively. The interaction with hnRNP E2 is independent of the microRNA's seed sequence and it leads to release of CEBPA mRNA from hnRNP E2-mediated translational inhibition. Altogether, these data reveal the dual ability of a microRNA to control cell fate both through base pairing with mRNA targets and through a decoy activity that interferes with the function of regulatory proteins.
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Ribonucleoproteínas Nucleares Heterogéneas/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , MicroARNs/metabolismo , Animales , Crisis Blástica , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Línea Celular Tumoral , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Ratones , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Complejo Silenciador Inducido por ARN/metabolismoRESUMEN
Given the selection of elderly patients with AML in first complete remission (CR1) the advantage of consolidation with allogeneic hematopoietic cell transplantation (HCT) over chemotherapy is still unclear. Newly diagnosed AML patients in CR1 aged 60-75 years were registered and a donor search initiated. After one consolidation cycle, patients with a matched donor were randomized to HCT with fludarabine/lowdose total body irradiation and cyclosporine/mycophenolate mofetil immunosuppression or conventional non-HCT. Primary outcome was restricted mean leukemia-free survival (RM-LFS) up to five years. Between 2010 and 2017, 245 patients (median age 67 years) were registered at CR1. After one consolidation, 26.9% of patients failed inclusion criteria. Of the 179 (73%) patients still on study, 75.4% had an HLA identical donor. Ten ineligible patients were excluded, and 125 randomized to HCT (n=83) or non-HCT (n=42). The primary outcome RM-LFS up to 5 years was 24.5 months (95%CI:18.9-30.1) in the HCT and 15.6 months (95%CI:10.4-20.8) in the non-HCT arm (p=0.022) due to a decrease in cumulative relapse incidence from 91.1 (95%CI:80.7-100.0) after non-HCT to 37.8 (95%CI:27.2-48.4)% after HCT (p.
RESUMEN
BACKGROUND: The incorporation of anti-CD38 monoclonal antibodies (mAb) in induction regimens of newly diagnosed transplant-eligible multiple myeloma (MM) patients has been established as a new standard. However, the optimal strategy of stem cell mobilization in this context is not yet clear. STUDY DESIGN AND METHODS: From May 2020 till September 2022, we retrospectively reviewed patients receiving anti-CD38 mAb-based induction therapy followed by stem cell mobilization either in a steady-state protocol (SSM) using 10 µg/kg granulocyte colony-stimulating factor (G-CSF) for 5 days or in a chemotherapy-based protocol (CM) using 1-4 g/m2 cyclophosphamide and G-CSF. RESULTS: Overall, 85 patients (median age 61 years) were included in the analysis. In total, 90 mobilization attempts were performed, 42 with SSM and 48 with CM. There was no significant difference in the median concentration of CD34+ cells in peripheral blood (PB) prior to apheresis between SSM and CM (61/µL vs. 55.4/µL; p = .60). Cumulative CD34+ yields did not differ between the groups with median of 6.68 and 6.75 × 106 /kg body weight, respectively (p = .35). The target yield (≥4 × 106 CD34+ cells/kg body weight) was reached in 88% (CM) and 86% (SSM), with a high proportion even after a single apheresis session (76% vs. 75%). Plerixafor was found to be more frequently used in SSM (52%) than in CM (23%; p < .01). A total of 83 patients underwent autologous transplantation and all were engrafted. CONCLUSIONS: Stem cell collection in patients undergoing anti-CD38-based induction therapy is feasible with either CM or SSM, although SSM more frequently requires plerixafor.
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Antineoplásicos , Trasplante de Células Madre Hematopoyéticas , Compuestos Heterocíclicos , Mieloma Múltiple , Humanos , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Movilización de Célula Madre Hematopoyética/métodos , Quimioterapia de Inducción , Estudios Retrospectivos , Compuestos Heterocíclicos/uso terapéutico , Antineoplásicos/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/farmacología , Antígenos CD34/metabolismo , Trasplante Autólogo , Peso CorporalRESUMEN
A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60-87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45-64)) and the study group arms (53% (95%CI: 47-60) and 59% (95%CI: 58-63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7-14.0) in the CSA, 7.6% (95%CI: 4.5-12.8) in study group A and 11.1% (95%CI: 9.0-13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0-26.9), 17.0% (95%CI: 2.0-23.9), and 19.5% (95%CI: 16.7-22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA.
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Leucemia Mieloide Aguda , Mitoxantrona , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Citarabina/uso terapéutico , Daunorrubicina/efectos adversos , Supervivencia sin Enfermedad , Leucemia Mieloide Aguda/tratamiento farmacológico , Mitoxantrona/efectos adversos , Pronóstico , Inducción de RemisiónRESUMEN
BACKGROUND: Pegfilgrastim is a covalently bound conjugate of filgrastim and mono-methoxypolyethylene glycol with a longer half-life. STUDY DESIGN AND METHODS: We report on phase II prospective monocentric trial examining the feasibility of stem cell mobilization with 12 mg single dose pegfilgrastim in related donors. The objectives were to determine the optimal collection day, defined as CD34+ concentration in peripheral blood (PB) >50 cells/µl, the number of donors collected with single leukapheresis, and the peak level of pegfilgrastim in donor-serum. Furthermore, the cell composition of grafts was assessed and compared to published data. RESULTS: The results included about 28 matched related donors. The median pegfilgrastim serum level remained >200 ng/mL for 48 hours before declining, with the maximal measured concentration of 259.49 ng/ml 24 h after application. The median white blood cell count and CD34 count in PB peaked on day four with 52.6 (range 22.8-85.0) Gpt/l and 66.25 (range 22.9-136.6) cells/µl, respectively. A CD34+ count >50 cells/µl on day four was detected in 75% of donors. 79% of the donors underwent a single collection. Conventional filgrastim was administered additionally in two donors, due to insufficient CD 34+ concentration in PB. 89% of donors showed CD34+ yields ≥4 (median 6.5, range 4.6-14.5) × 10/kg body weight of the recipient. All grafts were administered without rejections. DISCUSSION: The results of this trial showed that stem cell mobilization with pegfilgrastim is a feasible, and attractive option. This is the first trial presenting the kinetics of pegfilgrastim serum levels in healthy donors.
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Movilización de Célula Madre Hematopoyética , Trasplante de Células Madre Hematopoyéticas , Antígenos CD34/metabolismo , Filgrastim , Factor Estimulante de Colonias de Granulocitos/farmacología , Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Polietilenglicoles , Estudios Prospectivos , Proteínas Recombinantes , HermanosRESUMEN
BACKGROUND: Ewing sarcoma is one of the most frequent soft-tissue tumors in pediatric patients. The current treatment protocols recommend stem cell apheresis (SCA) after completion of the second course of induction therapy with vincristine, ifosfamide, doxorubicine, and etoposide (VIDE). The feasibility of SCA and graft compositions in adult patients with Ewing sarcoma have not been previously analyzed. METHODS AND MATERIALS: The authors analyzed 29 stem cell collections of 19 adult patients (9 male, 10 female) at a median age of 27 (range 19-53) years mobilized after VIDE (n = 17), cyclophosphamide/topotecan (n = 1) or vincristine, dactinomycin and ifosfamide (n = 1) chemotherapy. All patients were mobilized with filgrastim 5 µg/kg twice daily from day +7 of chemotherapy. The collections were performed if CD34+ cell count in peripheral blood was >10/µL. The target yields were ≥4×106 CD34+ cells/kg body weight. RESULTS: Median CD34+ cells/µL in peripheral blood before SCA were 45.8 (range 6.7-614.4)/µL. The median cumulative yields were 10.6 (range 1.5-38.8) CD34+ cells/kg body weight and ≥2×106 in all but two patients (89%). CD34, CD3, and CD56 yields in collections after the third VIDE and after later courses did not differ. Four patients underwent high-dose therapy with autologous transplantation, and all were engrafted. DISCUSSION: Stem cell mobilization is feasible in most Ewing sarcoma patients. Additionally, the present study's data suggest that it is safe to postpone stem cell collection to a later VIDE chemotherapy cycle if medically indicated.
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Trasplante de Células Madre Hematopoyéticas , Sarcoma de Ewing , Adulto , Antígenos CD34 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Peso Corporal , Niño , Doxorrubicina/efectos adversos , Etopósido , Femenino , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Movilización de Célula Madre Hematopoyética/métodos , Humanos , Ifosfamida/efectos adversos , Masculino , Persona de Mediana Edad , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/etiología , Células Madre , Vincristina/efectos adversos , Vincristina/uso terapéutico , Adulto JovenRESUMEN
The SRSF2 mutations are frequently found in acute myeloid leukemia (AML) and mostly affect the P95 residue. Mutations in this splicing factor mediate abnormal splicing associated with exon skipping events, including EZH2 as a crucial target. While SRSF2 mutations are enriched in secondary AML and associated with worse outcomes following chemotherapy consolidation, very little is known about the associated biological and clinical implications in AML patients consolidated with allogeneic hematopoietic stemcell transplantation (HSCT). Here we retrospectively analyzed 263 adult AML patients who received an allogeneic HSCT regarding the biological and clinical implications of the SRSF2 mutation status at diagnosis and in morphologic remission at HSCT. We found 12.5% of the patients to be SRSF2 mutated at diagnosis. Mutated patients had increased EZH2 missplicing events with P95H likely driving this pathobiology most effectively. However, the amount of EZH2 missplicing events, as a functional surrogate marker did not associate with relevant biological or clinical characteristics. We observed a persistence of mutations in remission before HSCT in the majority (93%) of SRSF2 mutated AML patients. Importantly, the variant allele frequency (VAF) levels of SRSF2 mutations in remission at HSCT did not correlate with outcomes following HSCT consolidation, limiting the applicability of SRSF2 mutations as a marker for residual AML disease. Following allogeneic HSCT SRSF2 mutated AML patients experienced a 2-year overall survival of 77%, indicating that SRSF2 mutated AML patients may benefit from HSCT consolidation.
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Leucemia Mieloide Aguda/genética , Factores de Empalme Serina-Arginina/genética , Adulto , Anciano , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Mutación , Estudios Retrospectivos , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
For most acute myeloid leukemia (AML) patients, an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of sustained remissions and long-term survival. At diagnosis, high expression of the AML-associated genes BAALC (brain and acute leukemia, cytoplasmic) and MN1 (meningioma-1) were repeatedly linked to inferior outcomes in patients consolidated with chemotherapy while data for patients receiving HSCT remain limited. Using clinically applicable digital droplet PCR assays, we analyzed the diagnostic BAALC/ABL1 and MN1/ABL1 copy numbers in 302 AML patients. High BAALC/ABL1 and MN1/ABL1 copy numbers associated with common adverse prognostic factors at diagnosis. However, while high diagnostic copy numbers of both genes associated with shorter event free survival (EFS) and overall survival (OS) in patients receiving chemotherapy, there was no prognostic impact in patients undergoing HSCT. Our data suggests that the adverse prognostic impact of high BAALC and MN1 expression are mitigated by allogeneic HSCT. But preHSCT BAALC/ABL1 and MN1/ABL1 assessed in remission prior to HSCT remained prognosticators for EFS and OS independent of the diagnostic expression status. Whether allogeneic HSCT may improve survival for AML patients with high diagnostic BAALC or MN1 expression should be investigated prospectively and may improve informed decisions towards individualized consolidation options in AML.
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Médula Ósea/patología , Leucemia Mieloide Aguda/terapia , Proteínas de Neoplasias/genética , Trasplante de Células Madre de Sangre Periférica , Transactivadores/genética , Proteínas Supresoras de Tumor/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Aloinjertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Médula Ósea/química , Terapia Combinada , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/biosíntesis , Reacción en Cadena de la Polimerasa/métodos , Pronóstico , Proteínas Proto-Oncogénicas c-abl/genética , Transactivadores/biosíntesis , Resultado del Tratamiento , Proteínas Supresoras de Tumor/biosíntesis , Adulto JovenRESUMEN
OPINION STATEMENT: The expanding availability of minimal or more precisely measurable residual disease (MRD) assessment in acute myeloid leukemia (AML) with its possible implications for therapeutic decisions is of high interest to clinicians treating AML patients. A variety of mostly retrospective studies have shown that AML patients with a positive MRD test, assessed by different techniques at defined cutoffs and time-points, are at significantly higher risk of relapse and experience shorter overall survival compared to MRD-negative patients. How this valuable information may be adapted in the daily routine of patients' treatment to distinguish individuals who need more aggressive therapy from the ones who can be spared additional therapy to avoid treatment-related toxicities is still being investigated. With the exception of MRD analyses in acute promyelocitic leukemia (APL), the clinical implications of MRD tests for the individual AML patient are still mostly unknown. We currently lack hard evidence that MRD-based therapy modulation during treatment or pre-emptive intervention in MRD-positive patients after therapy would improve outcomes in non-APL AML patients. These questions will be evaluated in prospective randomized clinical trials. Today, however, some conclusions with regard to MRD assessment in AML can be drawn from the published data and are reviewed in this article.
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Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Neoplasia Residual/terapia , Biomarcadores de Tumor , Toma de Decisiones Clínicas , Terapia Combinada , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Humanos , Leucemia Mieloide Aguda/etiología , Pronóstico , Resultado del TratamientoRESUMEN
Myelodysplastic syndrome (MDS) is a highly heterogeneous clonal hematopoietic disorder. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment and is of particular interest in patients at high risk for progression to acute myeloid leukemia (AML). In MDS, CD34+/CD38- cells possess MDS stem cell potential, and secondary AML (sAML) clones originate from the MDS disease stage. However, the prognostic impact of the pretreatment stem cell population burden in MDS remains unknown. We retrospectively analyzed the prognostic impact of the pretreatment CD34+/CD38- cell burden in 124 MDS patients who received allogeneic HSCT at our institution. A high pretreatment bone marrow CD34+/CD38- cell burden (≥1%) was associated with worse genetic risk and a higher incidence of blast excess. Patients with a high CD34+/CD38- cell burden had a significantly higher cumulative incidence of MDS relapse, a higher cumulative incidence of secondary AML, and a trend for shorter overall survival after allogeneic HSCT. In multivariable analyses this prognostic impact was shown to be independent of other clinical and cytogenetic risk factors in MDS. Patients suffering MDS relapse or progression to AML also had a higher pre-treatment CD34+/CD38- cell burden as a continuous variable. The observed prognostic impact is likely mediated by MDS stem cells within the CD34+/CD38- cell population initiating MDS relapse or progression to AML. New therapeutic strategies targeting MDS stem cells might improve outcomes.
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Antígenos CD34 , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas , Síndromes Mielodisplásicos , ADP-Ribosil Ciclasa 1 , Adulto , Anciano , Aloinjertos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapia , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Allogeneic stem cell transplantation (HSCT) remains the only curative treatment for myelodysplastic syndromes (MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients. The introduction of reduced intensity (RIC) and non-myeloablative (NMA) conditioning enabled HSCT in older or comorbid individuals representing the majority of patients. Studies comparing RIC and NMA conditioning are limited. We retrospectively analyzed 151 MDS or MDS/MPN patients older than 50 years who received NMA- or RIC-HSCT. Patients younger or older than 65 years at HSCT were analyzed separately. Patients receiving RIC-HSCT or NMA-HSCT were balanced in factors reflecting disease aggressiveness and the HCT-CI comorbidity score. The NMA conditioned patients had a higher incidence of graft rejection and chronic graft-vs-host disease. Cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and overall survival (OS), did not differ significantly with regard to the conditioning regime in the whole cohort. In patients <65 years at HSCT, NMA conditioning associated with higher NRM and shorter OS by trend, while CIR was similar in both groups. In multivariable analyzes, the conditioning regimen remained a prognostic factor for NRM and OS in patients <65 years at HSCT. In MDS patients NMA and RIC conditioning result in similar disease control, but especially patients <65 years may benefit from RIC-HSCT.
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Trasplante de Células Madre de Sangre Periférica , Acondicionamiento Pretrasplante/métodos , Factores de Edad , Anciano , Anciano de 80 o más Años , Busulfano/administración & dosificación , Busulfano/efectos adversos , Busulfano/análogos & derivados , Comorbilidad , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Inmunosupresores/uso terapéutico , Estimación de Kaplan-Meier , Persona de Mediana Edad , Agonistas Mieloablativos/administración & dosificación , Agonistas Mieloablativos/efectos adversos , Síndromes Mielodisplásicos/epidemiología , Síndromes Mielodisplásicos/terapia , Trastornos Mieloproliferativos/epidemiología , Trastornos Mieloproliferativos/terapia , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Modelos de Riesgos Proporcionales , Recurrencia , Estudios Retrospectivos , Acondicionamiento Pretrasplante/efectos adversos , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/análogos & derivados , Irradiación Corporal TotalRESUMEN
Allogeneic hematopoietic stem cell transplantation is an established consolidation therapy for patients with acute myeloid leukemia. However, relapse after transplantation remains a major clinical problem resulting in poor prognosis. Thus, detection of measurable ("minimal") residual disease to identify patients at high risk of relapse is essential. A feasible method to determine measurable residual disease may be digital droplet PCR (ddPCR) that allows absolute quantification with high sensitivity and specificity without the necessity of standard curves. Using ddPCR, we analyzed pre-transplant peripheral blood and bone marrow of 51 NPM1-mutated acute myeloid leukemia patients transplanted in complete remission or complete remission with incomplete recovery. Mutated NPM1 measurable residual disease-positive patients had higher cumulative incidence of relapse (P < 0.001) and shorter overall survival (P = 0.014). Restricting the analyses to patients receiving non-myeloablative conditioning, mutated NPM1 measurable residual disease positivity is associated with higher cumulative incidence of relapse (P < 0.001) and shorter overall survival (P = 0.006). Positive mutated NPM1 measurable residual disease status determined by ddPCR before allogeneic stem cell transplantation is associated with worse prognosis independent of other known prognostic markers-also for those receiving non-myeloablative conditioning. In the future, mutated NPM1 measurable residual disease status determined by ddPCR might guide treatment and improve patients' outcomes.
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Leucemia Mieloide Aguda/patología , Mutación , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Reacción en Cadena de la Polimerasa/métodos , Cuidados Preoperatorios , Adulto , Anciano , Aloinjertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/sangre , Médula Ósea/química , Trasplante de Médula Ósea , Proteínas Potenciadoras de Unión a CCAAT/análisis , Terapia Combinada , ADN de Neoplasias/genética , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/análisis , Proteínas de Neoplasias/sangre , Neoplasia Residual , Proteínas Nucleares/análisis , Proteínas Nucleares/sangre , Nucleofosmina , Trasplante de Células Madre de Sangre Periférica , Pronóstico , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Sensibilidad y Especificidad , Acondicionamiento Pretrasplante/métodos , Resultado del Tratamiento , Tirosina Quinasa 3 Similar a fms/análisisRESUMEN
Allogeneic hematopoietic cell transplantation (HCT) is an important treatment for many severe hematologic disorders; however, HCT can be associated with significant complications, including organ toxicity, graft-versus-host disease, and relapse. Another serious, but rare, complication is the transmission of hematologic and nonhematologic diseases from the donor to the recipient. With older donors, the risk of an abnormality may be increased. Here we describe the transmission of an inversion 3 constitutional cytogenetic abnormality from an unrelated donor to a recipient, and review the clinical implications of the discovery of donor-derived constitutional cytogenetic abnormalities.
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Inversión Cromosómica , Cromosomas Humanos Par 3 , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Mieloide Aguda/terapia , Policitemia Vera/terapia , Donante no Emparentado , Progresión de la Enfermedad , Humanos , Cariotipo , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Policitemia Vera/complicaciones , Policitemia Vera/genética , Policitemia Vera/patología , Receptores de Trasplantes , Trasplante HomólogoRESUMEN
In acute myeloid leukemia (AML), leukemia-initiating cells exist within the CD34+/CD38- cell compartment. They are assumed to be more resistant to chemotherapy, enriched in minimal residual disease cell populations, and responsible for relapse. Here we evaluated clinical and biological associations and the prognostic impact of a high diagnostic CD34+/CD38- cell burden in 169 AML patients receiving an allogeneic stem cell transplantation in complete remission. Here, the therapeutic approach is mainly based on immunological graft-versus-leukemia effects. Percentage of bone marrow CD34+/CD38- cell burden at diagnosis was measured using flow cytometry and was highly variable (median 0.5%, range 0%-89% of all mononuclear cells). A high CD34+/CD38- cell burden at diagnosis associated with worse genetic risk and secondary AML. Patients with a high CD34+/CD38- cell burden had shorter relapse-free and overall survival which may be mediated by residual leukemia-initiating cells in the CD34+/CD38- cell population, escaping the graft-versus-leukemia effect after allogeneic transplantation. Evaluating the CD34+/CD38- cell burden at diagnosis may help to identify patients at high risk of relapse after allogeneic transplantation. Further studies to understand leukemia-initiating cell biology and develop targeting therapies to improve outcomes of AML patients are needed.
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ADP-Ribosil Ciclasa 1/análisis , Antígenos CD34/análisis , Leucemia Mieloide Aguda/patología , Células Madre Neoplásicas/patología , Adulto , Anciano , Aloinjertos , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Recurrencia , Tasa de Supervivencia , Adulto JovenRESUMEN
Neuroblastoma rat sarcoma (RAS) viral oncogene homolog (NRAS), a small GTPase, is one of the most thoroughly studied oncogenes that controls cell growth, differentiation, and survival by facilitating signal transduction. Here, we identify four novel naturally occurring NRAS isoforms (isoforms 2-5) in addition to the canonical isoform (isoform 1). Expression analyses performed on a panel of several different human malignancies and matching normal tissue revealed distinct isoform expression patterns. Two of the novel isoforms were found in the nucleus and cytoplasm, whereas the others were exclusively cytoplasmic. The isoforms varied in their binding affinities to known downstream targets and differentially regulated the RAS signaling pathway. Strikingly, forced expression of isoform 5, which encodes only a 20-aa peptide, led to increased cell proliferation and to transformation by activation of known NRAS targets. These discoveries open new avenues in the study of NRAS.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Transformación Celular Neoplásica/genética , GTP Fosfohidrolasas/genética , Regulación Neoplásica de la Expresión Génica/genética , Proteínas de la Membrana/genética , Isoformas de Proteínas/genética , Transducción de Señal/genética , Animales , Secuencia de Bases , Western Blotting , Células COS , Chlorocebus aethiops , Clonación Molecular , Cartilla de ADN/genética , Humanos , Inmunoprecipitación , Ratones , Microscopía Confocal , Datos de Secuencia Molecular , Células 3T3 NIH , Análisis de Secuencia de ADN , Estadísticas no ParamétricasAsunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Adulto , Anciano , Humanos , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/genética , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/etiología , Recurrencia Local de Neoplasia/genética , Neoplasia Residual , Factores de Riesgo , Trasplante Homólogo , Adulto JovenRESUMEN
The inv(16)(p13q22)/t(16;16)(p13;q22) in acute myeloid leukemia results in multiple CBFB-MYH11 fusion transcripts, with type A being most frequent. The biologic and prognostic implications of different fusions are unclear. We analyzed CBFB-MYH11 fusion types in 208 inv(16)/t(16;16) patients with de novo disease, and compared clinical and cytogenetic features and the KIT mutation status between type A (n = 182; 87%) and non-type A (n = 26; 13%) patients. At diagnosis, non-type A patients had lower white blood counts (P = .007), and more often trisomies of chromosomes 8 (P = .01) and 21 (P < .001) and less often trisomy 22 (P = .02). No patient with non-type A fusion carried a KIT mutation, whereas 27% of type A patients did (P = .002). Among the latter, KIT mutations conferred adverse prognosis; clinical outcomes of non-type A and type A patients with wild-type KIT were similar. We also derived a fusion-type-associated global gene-expression profile. Gene Ontology analysis of the differentially expressed genes revealed-among others-an enrichment of up-regulated genes involved in activation of caspase activity, cell differentiation and cell cycle control in non-type A patients. We conclude that non-type A fusions associate with distinct clinical and genetic features, including lack of KIT mutations, and a unique gene-expression profile.
Asunto(s)
Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas c-kit/genética , Adolescente , Adulto , Anciano , Inversión Cromosómica , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutación , Transcriptoma , Adulto JovenRESUMEN
Recently, we showed that increased miR-181a expression was associated with improved outcomes in cytogenetically normal acute myeloid leukemia (CN-AML). Interestingly, miR-181a expression was increased in CN-AML patients harboring CEBPA mutations, which are usually biallelic and associate with better prognosis. CEBPA encodes the C/EBPα transcription factor. We demonstrate here that the presence of N-terminal CEBPA mutations and miR-181a expression are linked. Indeed, the truncated C/EBPα-p30 isoform, which is produced from the N-terminal mutant CEBPA gene or from the differential translation of wild-type CEBPA mRNA and is commonly believed to have no transactivation activity, binds to the miR-181a-1 promoter and up-regulates the microRNA expression. Furthermore, we show that lenalidomide, a drug approved for myelodysplastic syndromes and multiple myeloma, enhances translation of the C/EBPα-p30 isoform, resulting in higher miR-181a levels. In xenograft mouse models, ectopic miR-181a expression inhibits tumor growth. Similarly, lenalidomide exhibits antitumorigenic activity paralleled by increased miR-181a expression. This regulatory pathway may explain an increased sensitivity to apoptosis-inducing chemotherapy in subsets of AML patients. Altogether, our data provide a potential explanation for the improved clinical outcomes observed in CEBPA-mutated CN-AML patients, and suggest that lenalidomide treatment enhancing the C/EBPα-p30 protein levels and in turn miR-181a may sensitize AML blasts to chemotherapy.