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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
The chronic phase of chronic myeloid leukemia (CP-CML) is characterized by the excessive production of maturating myeloid cells. As CML stem/progenitor cells (LSPCs) are poised to cycle and differentiate, LSPCs must balance conservation and differentiation to avoid exhaustion, similar to normal hematopoiesis under stress. Since BCR-ABL1 tyrosine kinase inhibitors (TKIs) eliminate differentiating cells but spare BCR-ABL1-independent LSPCs, understanding the mechanisms that regulate LSPC differentiation may inform strategies to eliminate LSPCs. Upon performing a meta-analysis of published CML transcriptomes, we discovered that low expression of the MS4A3 transmembrane protein is a universal characteristic of LSPC quiescence, BCR-ABL1 independence, and transformation to blast phase (BP). Several mechanisms are involved in suppressing MS4A3, including aberrant methylation and a MECOM-C/EBPε axis. Contrary to previous reports, we find that MS4A3 does not function as a G1/S phase inhibitor but promotes endocytosis of common ß-chain (ßc) cytokine receptors upon GM-CSF/IL-3 stimulation, enhancing downstream signaling and cellular differentiation. This suggests that LSPCs downregulate MS4A3 to evade ßc cytokine-induced differentiation and maintain a more primitive, TKI-insensitive state. Accordingly, knockdown (KD) or deletion of MS4A3/Ms4a3 promotes TKI resistance and survival of CML cells ex vivo and enhances leukemogenesis in vivo, while targeted delivery of exogenous MS4A3 protein promotes differentiation. These data support a model in which MS4A3 governs response to differentiating myeloid cytokines, providing a unifying mechanism for the differentiation block characteristic of CML quiescence and BP-CML. Promoting MS4A3 reexpression or delivery of ectopic MS4A3 may help eliminate LSPCs in vivo.
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Proteínas de Ciclo Celular/metabolismo , Endocitosis , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Proteínas de la Membrana/metabolismo , Receptores de Citocinas/metabolismo , Animales , Proteínas de Ciclo Celular/genética , Regulación hacia Abajo , Regulación Leucémica de la Expresión Génica , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Proteínas de la Membrana/genética , Ratones , Transcriptoma , Células Tumorales CultivadasRESUMEN
26S proteasome non-ATPase subunits 1 (PSMD1) and 3 (PSMD3) were recently identified as prognostic biomarkers and potential therapeutic targets in chronic myeloid leukemia (CML) and multiple solid tumors. In the present study, we analyzed the expression of 19S proteasome subunits in acute myeloid leukemia (AML) patients with mutations in the FMS-like tyrosine kinase 3 (FLT3) gene and assessed their impact on overall survival (OS). High levels of PSMD3 but not PSMD1 expression correlated with a worse OS in FLT3-mutated AML. Consistent with an oncogenic role for PSMD3 in AML, shRNA-mediated PSMD3 knockdown impaired colony formation of FLT3+ AML cell lines, which correlated with increased OS in xenograft models. While PSMD3 regulated nuclear factor-kappa B (NF-κB) transcriptional activity in CML, we did not observe similar effects in FLT3+ AML cells. Rather, proteomics analyses suggested a role for PSMD3 in neutrophil degranulation and energy metabolism. Finally, we identified additional PSMD subunits that are upregulated in AML patients with mutated versus wild-type FLT3, which correlated with worse outcomes. These findings suggest that different components of the 19S regulatory complex of the 26S proteasome can have indications for OS and may serve as prognostic biomarkers in AML and other types of cancers.
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Leucemia Mieloide Aguda , Tirosina Quinasa 3 Similar a fms , Humanos , Tirosina Quinasa 3 Similar a fms/genética , Complejo de la Endopetidasa Proteasomal/genética , Pronóstico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Mutación , OncogenesRESUMEN
BACKGROUND: The Texas/Chihuahua (US/Mexico) border is a medically underserved region with many reported barriers for health care access. Although Hispanic ethnicity is associated with health disparities for many different diseases, the population-based estimates of incidence and survival for patients with blood cancer along the border are unknown. The authors hypothesized that Hispanic ethnicity and border proximity is associated with poor blood cancer outcomes. METHODS: Data from the Texas Cancer Registry (1995-2016) were used to investigate the primary exposures of patient ethnicity (Hispanic vs non-Hispanic) and geographic location (border vs non-border). Other confounders and covariates included sex, age, year of diagnosis, rurality, insurance status, poverty indicators, and comorbidities. The Mantel-Haenszel method and Cox regression analyses were used to determine adjusted effects of ethnicity and border proximity on the relative risk (RR) and survival of patients with different blood cancer types. RESULTS: Hispanic patients were diagnosed at a younger age than non-Hispanic patients and presented with increased comorbidities. Whereas non-Hispanics had a higher incidence of developing blood cancer compared with Hispanics overall, Hispanics demonstrated a higher incidence of acute lymphoblastic leukemia (RR, 1.92; 95% CI, 1.79-2.08; P < .001) with worse outcomes. Hispanics from the Texas/Chihuahua border demonstrated a higher incidence of chronic myeloid leukemia (RR, 1.28; 95% CI, 1.07-1.51; P = .02) and acute myeloid leukemia (RR, 1.17; 95% CI, 1.04-1.33; P = .0009) compared with Hispanics living elsewhere in Texas. CONCLUSIONS: Hispanic ethnicity and border proximity were associated with a poor presentation and an adverse prognosis despite the younger age of diagnosis. Future studies should explore differences in disease biology and treatment strategies that could drive these regional disparities.
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Enfermedades Hematológicas/etnología , Hispánicos o Latinos , Área sin Atención Médica , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Comorbilidad , Femenino , Accesibilidad a los Servicios de Salud , Enfermedades Hematológicas/epidemiología , Enfermedades Hematológicas/mortalidad , Humanos , Incidencia , Cobertura del Seguro , Leucemia Mielógena Crónica BCR-ABL Positiva/epidemiología , Leucemia Mielógena Crónica BCR-ABL Positiva/etnología , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/etnología , Leucemia Mieloide Aguda/mortalidad , Leucemia Promielocítica Aguda/epidemiología , Leucemia Promielocítica Aguda/etnología , Leucemia Promielocítica Aguda/mortalidad , Masculino , México/etnología , Persona de Mediana Edad , Síndromes Mielodisplásicos/epidemiología , Síndromes Mielodisplásicos/etnología , Síndromes Mielodisplásicos/mortalidad , Trastornos Mieloproliferativos/epidemiología , Trastornos Mieloproliferativos/etnología , Trastornos Mieloproliferativos/mortalidad , Pobreza , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/etnología , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Sistema de Registros , Análisis de Regresión , Población Rural , Factores Sexuales , Texas , Adulto JovenRESUMEN
Normal human bone marrow cells are critical for studies of hematopoiesis and as controls to assess toxicity. As cells from commercial vendors are expensive, many laboratories resort to cancer-free bone marrow specimens obtained during staging or to umbilical cord blood cells, which may be abnormal or reflect a much younger age group compared to the disease samples under study. We piloted the use of femoral heads as an alternative and inexpensive source of normal bone marrow. Femoral heads were obtained from 21 successive patients undergoing elective hip arthroplasty. Mononuclear cells (MNCs) were purified with Ficoll, and CD3+, CD14+, and CD34+ cells were purified with antibody-coated microbeads. The median yield of MNCs was 8.95 × 107 (range, 1.62 × 105-2.52 × 108), and the median yield of CD34+ cells was 1.40 × 106 (range, 3.60 × 105-9.90 × 106). Results of downstream applications including qRT-PCR, colony-forming assays, and ex vivo proliferation analysis were of high quality and comparable to those obtained with standard bone marrow aspirates. We conclude that femoral heads currently discarded as medical waste are a cost-efficient source of bone marrow cells for research use.
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Cabeza Femoral/citología , Células Madre Hematopoyéticas/citología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD34/metabolismo , Artroplastia de Reemplazo de Cadera , Estudios de Casos y Controles , Sangre Fetal/citología , Células Madre Hematopoyéticas/metabolismo , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/metabolismo , Persona de Mediana EdadRESUMEN
Despite significant advances in the treatment of myeloid malignancies, many patients become resistant to therapy and ultimately succumb to their disease. Accumulating evidence over the past several years has suggested that the inadequacy of many leukaemia therapies results from their failure to target the leukaemic stem cell (LSC). For this reason, the LSC population currently represents the most critical target in the treatment of myeloid malignancies. However, while LSCs are ideal targets in the treatment of these diseases, they are also the most difficult population to target. This is due to both their heterogeneity within the LSC population, and also their phenotypic similarities with normal haematopoietic stem cells. This review will highlight the current landscape surrounding LSC biology in myeloid malignancies, with a focus on altered energy metabolism, and how that knowledge is being translated into clinical advances for the treatment of chronic and acute myeloid leukaemia and myelodysplastic syndromes.
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Antineoplásicos/farmacología , Metabolismo Energético , Leucemia Mieloide/etiología , Leucemia Mieloide/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor , Ensayos Clínicos como Asunto , Resistencia a Antineoplásicos/genética , Hematopoyesis , Células Madre Hematopoyéticas/metabolismo , Humanos , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/tratamiento farmacológico , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/terapia , Transducción de Señal , Resultado del TratamientoRESUMEN
FLT3-ITD+ acute myeloid leukemia (AML) accounts for â¼25% of all AML cases and is a subtype that carries a poor prognosis. microRNA-155 (miR-155) is specifically overexpressed in FLT3-ITD+ AML compared with FLT3 wild-type (FLT3-WT) AML and is critical for the growth of FLT3-ITD+ AML cells in vitro. However, miR-155's role in regulating FLT3-ITD-mediated disease in vivo remains unclear. In this study, we used a genetic mouse model to determine whether miR-155 influences the development of FLT3-ITD-induced myeloproliferative disease. Results indicate that miR-155 promotes FLT3-ITD-induced myeloid expansion in the bone marrow, spleen, and peripheral blood. Mechanistically, miR-155 increases proliferation of the hematopoietic stem and progenitor cell compartments by reducing the growth-inhibitory effects of the interferon (IFN) response, and this involves targeting of Cebpb. Consistent with our observations in mice, primary FLT3-ITD+ AML clinical samples have significantly higher miR-155 levels and a lower IFN response compared with FLT3-WT AML samples. Further, inhibition of miR-155 in FLT3-ITD+ AML cell lines using CRISPR/Cas9, or primary FLT3-ITD+ AML samples using locked nucleic acid antisense inhibitors, results in an elevated IFN response and reduces colony formation. Altogether, our data reveal that miR-155 collaborates with FLT3-ITD to promote myeloid cell expansion in vivo and that this involves a multitarget mechanism that includes repression of IFN signaling.
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Interferones/biosíntesis , MicroARNs/genética , Trastornos Mieloproliferativos/etiología , Tirosina Quinasa 3 Similar a fms/genética , Animales , Sistemas CRISPR-Cas , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Mutantes , MicroARNs/antagonistas & inhibidores , Mutación , Células Progenitoras Mieloides/inmunología , Células Progenitoras Mieloides/patología , Mielopoyesis/genética , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/inmunología , Ensayo de Tumor de Célula MadreRESUMEN
The mechanisms underlying tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML) patients lacking explanatory BCR-ABL1 kinase domain mutations are incompletely understood. To identify mechanisms of TKI resistance that are independent of BCR-ABL1 kinase activity, we introduced a lentiviral short hairpin RNA (shRNA) library targeting â¼5000 cell signaling genes into K562(R), a CML cell line with BCR-ABL1 kinase-independent TKI resistance expressing exclusively native BCR-ABL1. A customized algorithm identified genes whose shRNA-mediated knockdown markedly impaired growth of K562(R) cells compared with TKI-sensitive controls. Among the top candidates were 2 components of the nucleocytoplasmic transport complex, RAN and XPO1 (CRM1). shRNA-mediated RAN inhibition or treatment of cells with the XPO1 inhibitor, KPT-330 (Selinexor), increased the imatinib sensitivity of CML cell lines with kinase-independent TKI resistance. Inhibition of either RAN or XPO1 impaired colony formation of CD34(+) cells from newly diagnosed and TKI-resistant CML patients in the presence of imatinib, without effects on CD34(+) cells from normal cord blood or from a patient harboring the BCR-ABL1(T315I) mutant. These data implicate RAN in BCR-ABL1 kinase-independent imatinib resistance and show that shRNA library screens are useful to identify alternative pathways critical to drug resistance in CML.
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Transporte Activo de Núcleo Celular , Proteínas de Fusión bcr-abl/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , ARN Interferente Pequeño/genética , Transporte Activo de Núcleo Celular/genética , Benzamidas/farmacología , Línea Celular Tumoral , Supervivencia Celular , Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/genética , Técnicas de Silenciamiento del Gen , Biblioteca de Genes , Humanos , Hidrazinas/farmacología , Mesilato de Imatinib , Células K562 , Carioferinas/antagonistas & inhibidores , Carioferinas/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Mutación , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/genética , Transducción de Señal , Triazoles/farmacología , Ensayo de Tumor de Célula Madre , Proteína de Unión al GTP ran/antagonistas & inhibidores , Proteína de Unión al GTP ran/genética , Proteína Exportina 1RESUMEN
BCR-ABL1 compound mutations can confer high-level resistance to imatinib and other ABL1 tyrosine kinase inhibitors (TKIs). The third-generation ABL1 TKI ponatinib is effective against BCR-ABL1 point mutants individually, but remains vulnerable to certain BCR-ABL1 compound mutants. To determine the frequency of compound mutations among chronic myeloid leukemia patients on ABL1 TKI therapy, in the present study, we examined a collection of patient samples (N = 47) with clear evidence of 2 BCR-ABL1 kinase domain mutations by direct sequencing. Using a cloning and sequencing method, we found that 70% (33/47) of double mutations detected by direct sequencing were compound mutations. Sequential, branching, and parallel routes to compound mutations were common. In addition, our approach revealed individual and compound mutations not detectable by direct sequencing. The frequency of clones harboring compound mutations with more than 2 missense mutations was low (10%), whereas the likelihood of silent mutations increased disproportionately with the total number of mutations per clone, suggesting a limited tolerance for BCR-ABL1 kinase domain missense mutations. We conclude that compound mutations are common in patients with sequencing evidence for 2 BCR-ABL1 mutations and frequently reflect a highly complex clonal network, the evolution of which may be limited by the negative impact of missense mutations on kinase function.
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Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Mutación Missense/genética , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Benzamidas , Clonación Molecular , Análisis Mutacional de ADN/métodos , Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/química , Regulación Leucémica de la Expresión Génica/genética , Humanos , Mesilato de Imatinib , Estructura Terciaria de ProteínaRESUMEN
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.
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Proteínas Potenciadoras de Unión a CCAAT/fisiología , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Factores Inmunológicos/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , MicroARNs/biosíntesis , Proteínas de Neoplasias/biosíntesis , ARN Neoplásico/biosíntesis , Talidomida/análogos & derivados , Adulto , Animales , Antimetabolitos Antineoplásicos/farmacología , Proteínas Potenciadoras de Unión a CCAAT/biosíntesis , Proteínas Potenciadoras de Unión a CCAAT/genética , Línea Celular Tumoral/efectos de los fármacos , Línea Celular Tumoral/metabolismo , Línea Celular Tumoral/trasplante , Citarabina/farmacología , Mutación del Sistema de Lectura , Humanos , Factores Inmunológicos/uso terapéutico , Células K562 , Lenalidomida , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , MicroARNs/genética , Proteínas de Neoplasias/genética , Mutación Puntual , Regiones Promotoras Genéticas/genética , Isoformas de Proteínas/biosíntesis , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiología , Estructura Terciaria de Proteína , ARN Neoplásico/genética , Proteínas Recombinantes de Fusión/fisiología , Talidomida/farmacología , Talidomida/uso terapéutico , Regulación hacia Arriba/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Introduction: The ubiquitin-proteasome system (UPS) is an intracellular organelle responsible for targeted protein degradation, which represents a standard therapeutic target for many different human malignancies. Bortezomib, a reversible inhibitor of chymotrypsin-like proteasome activity, was first approved by the FDA in 2003 to treat multiple myeloma and is now used to treat a number of different cancers, including relapsed mantle cell lymphoma, diffuse large B-cell lymphoma, colorectal cancer, and thyroid carcinoma. Despite the success, bortezomib and other proteasome inhibitors are subject to severe side effects, and ultimately, drug resistance. We recently reported an oncogenic role for non-ATPase members of the 19S proteasome in chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and several different solid tumors. In the present study, we hypothesized that ATPase members of the 19S proteasome would also serve as biomarkers and putative therapeutic targets in AML and multiple other cancers. Methods: We used data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) available at UALCAN and/or GEPIA2 to assess the expression and prognostic value of proteasome 26S subunit, ATPases 1-6 (PSMC1-6) of the 19S proteasome in cancer. UALCAN was also used to associate PSMC1-6 mRNA expression with distinct clinicopathological features. Finally, cBioPortal was employed to assess genomic alterations of PSMC genes across different cancer types. Results: The mRNA and protein expression of PSMC1-6 of the 19S proteasome were elevated in several cancers compared with normal controls, which often correlated with worse overall survival. In contrast, AML patients demonstrated reduced expression of these proteasome subunits compared with normal mononuclear cells. However, AML patients with high expression of PSMC2-5 had worse outcomes. Discussion: Altogether, our data suggest that components of the 19S proteasome could serve as prognostic biomarkers and novel therapeutic targets in AML and several other human malignancies.
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Prophylactic vaccination against infectious diseases is one of the most successful public health measures of our lifetime. More recently, therapeutic vaccination against established diseases such as cancer has proven to be more challenging. In the host, cancer cells evade immunologic regulation by multiple means, including altering the antigens expressed on their cell surface or recruiting inflammatory cells that repress immune surveillance. Nevertheless, recent clinical data suggest that two classes of antigens show efficacy for the development of anticancer vaccines: tumor-associated antigens and neoantigens. In addition, many different vaccines derived from antigens based on cellular, peptide/protein, and genomic components are in development to establish their efficacy in cancer therapy. Some vaccines have shown promising results, which may lead to favorable outcomes when combined with standard therapeutic approaches. This review provides an overview of the innate and adaptive immune systems, their interactions with cancer cells, and the development of various different vaccines for use in anticancer therapeutics.
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Tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 have turned chronic myeloid leukaemia (CML) from a fatal disease into a manageable condition for most patients. Despite improved survival, targeting drug-resistant leukaemia stem cells (LSCs) remains a challenge for curative CML therapy. Aberrant lipid metabolism can have a large impact on membrane dynamics, cell survival and therapeutic responses in cancer. While ceramide and sphingolipid levels were previously correlated with TKI response in CML, the role of lipid metabolism in TKI resistance is not well understood. We have identified downregulation of a critical regulator of lipid metabolism, G0/G1 switch gene 2 (G0S2), in multiple scenarios of TKI resistance, including (1) BCR::ABL1 kinase-independent TKI resistance, (2) progression of CML from the chronic to the blast phase of the disease, and (3) in CML versus normal myeloid progenitors. Accordingly, CML patients with low G0S2 expression levels had a worse overall survival. G0S2 downregulation in CML was not a result of promoter hypermethylation or BCR::ABL1 kinase activity, but was rather due to transcriptional repression by MYC. Using CML cell lines, patient samples and G0s2 knockout (G0s2-/- ) mice, we demonstrate a tumour suppressor role for G0S2 in CML and TKI resistance. Our data suggest that reduced G0S2 protein expression in CML disrupts glycerophospholipid metabolism, correlating with a block of differentiation that renders CML cells resistant to therapy. Altogether, our data unravel a new role for G0S2 in regulating myeloid differentiation and TKI response in CML, and suggest that restoring G0S2 may have clinical utility.
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Proteínas de Ciclo Celular , Resistencia a Antineoplásicos , Glicerofosfolípidos , Leucemia Mielógena Crónica BCR-ABL Positiva , Animales , Ratones , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/genética , Genes de Cambio , Glicerofosfolípidos/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Humanos , Proteínas de Ciclo Celular/genéticaRESUMEN
Although imatinib is firmly established as an effective therapy for newly diagnosed patients with chronic myeloid leukemia (CML), the field continues to advance on several fronts. In this minireview we cover recent results of second generation tyrosine kinase inhibitors in newly diagnosed patients, investigate the state of strategies to discontinue therapy and report on new small molecule inhibitors to tackle resistant disease, focusing on agents that target the T315I mutant of BCR-ABL. As a result of these advances, standard of care in frontline therapy has started to gravitate toward dasatinib and nilotinib, although more observation is needed to fully support this. Stopping therapy altogether remains a matter of clinical trials, and more must be learned about the mechanisms underlying the persistence of leukemic cells with treatment. However, there is good news for patients with the T315I mutation, as effective drugs such as ponatinib are on their way to regulatory approval. Despite these promising data, accelerated or blastic phase disease remains a challenge, possibly due to BCR-ABL-independent resistance.
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Antineoplásicos/administración & dosificación , Quimioterapia/métodos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Ensayos Clínicos como Asunto , Humanos , Resultado del TratamientoRESUMEN
Acute myeloid leukemia (AML) is a highly heterogeneous malignancy characterized by the clonal expansion of myeloid stem and progenitor cells in the bone marrow, peripheral blood, and other tissues. AML results from the acquisition of gene mutations or chromosomal abnormalities that induce proliferation or block differentiation of hematopoietic progenitors. A combination of cytogenetic profiling and gene mutation analyses are essential for the proper diagnosis, classification, prognosis, and treatment of AML. In the present review, we provide a summary of genomic abnormalities in AML that have emerged as both markers of disease and therapeutic targets. We discuss the abnormalities of RARA, FLT3, BCL2, IDH1, and IDH2, their significance as therapeutic targets in AML, and how various mechanisms cause resistance to the currently FDA-approved inhibitors. We also discuss the limitations of current genomic approaches for producing a comprehensive picture of the activated signaling pathways at diagnosis or at relapse in AML patients, and how innovative technologies combining genomic and functional methods will improve the discovery of novel therapeutic targets in AML. The ultimate goal is to optimize a personalized medicine approach for AML patients and possibly those with other types of cancers.
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Background: Population-based studies on Hodgkin's lymphoma (HL) have shown reduced survival in Hispanics and non-Hispanic Blacks compared with non-Hispanic Whites. To better understand the factors contributing to this outcome discrepancy, we retrospectively reviewed the charts of patients with HL diagnosed and treated at a single institution located along the Texas-Mexico border. Patients and Methods: We performed a retrospective chart review of all patients with HL treated at our institution over an 8-year period (2011-2018). The International Prognostic Score was calculated for all patients and results of positron-emission tomography (PET) scans (interim and end of treatment) were also recorded. Variables analyzed included tumor-related findings (stage, subtype of HL), treatment history (chemotherapy regimen including number of cycles, dose intensity and radiation treatments) and neutrophil to lymphocyte ratio. Quantitative variables were described using median, interquartile range, minimum and maximum observations. Categorical variables were described using frequency and proportions. Kaplan-Meier curves were used to show relapse-free survival. Results: A total of 24 patients were treated in the time frame, of whom 23 were Hispanic. All were treated with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) or an ABVD-like regimen. Dose intensity for chemotherapy exceeded 90%. After a median follow-up of 43 months, the relapse rate was 45.8%. Positive and negative predictive values for interim PET (0% and 50%) and end of therapy PET (80% and 58%) were suboptimal to allow for a PET-adapted therapeutic approach. Conclusion: Hispanics have a high relapse rate following ABVD which is not fully explained by universally accepted prognostic factors. Performance of PET scan in predicting outcomes of HL needs to be further studied and optimized before adopting a PET-adapted treatment paradigm for underserved Hispanic populations.
RESUMEN
Cancer is a challenging, multifaceted disease that involves a combination of biological and nonbiological factors. Aside from COVID-19, cancer is the second leading cause of death in the United States and the first among Hispanic Americans. The Hispanic population is the largest minority group in the United States, which is rapidly growing in size. Unfortunately, U.S. Hispanics and other minority groups experience many different health disparities, resulting in poor survival outcomes and a reduced quality of life. Factors such as genomic mutations, lower socioeconomic status, lack of education, reduced access to health care, comorbidities, and environmental factors all contribute to these health-care inequalities. In the context of blood cancer health disparities, Hispanic patients are often diagnosed at a younger age and have worse outcomes compared with non-Hispanic individuals. In this commentary, we highlight the existing knowledge about cancer health disparities in the Hispanic population, with a focus on chronic and acute leukemia. In our experience at the U.S./Mexican border, analysis of several different blood cancers demonstrated that younger Hispanic patients with acute lymphoid or myeloid leukemia have higher incidence rates and worse prognoses. A combined approach, involving improved health-care access and better knowledge of the underlying factors, will allow for more timely diagnoses and the development of intervention strategies aimed at reducing or eliminating the disparities.
Asunto(s)
Disparidades en Atención de Salud , Neoplasias Hematológicas/epidemiología , Leucemia/epidemiología , Femenino , Hispánicos o Latinos , Humanos , Masculino , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
Ever since the ubiquitin proteasome system was characterized, efforts have been made to manipulate its function to abrogate the progression of cancer. As a result, the anti-cancer drugs bortezomib, carfilzomib, and ixazomib targeting the 26S proteasome were developed to treat multiple myeloma, mantle cell lymphoma, and diffuse large B-cell lymphoma, among others. Despite success, adverse side effects and drug resistance are prominent, raising the need for alternative therapeutic options. We recently demonstrated that knockdown of the 19S regulatory components, 26S proteasome non-ATPase subunits 1 (PSMD1) and 3 (PSMD3), resulted in increased apoptosis of chronic myeloid leukemia (CML) cells, but had no effect on normal controls, suggesting they may be good targets for therapy. Therefore, we hypothesized that PSMD1 and PSMD3 are potential targets for anti-cancer therapeutics and that their relevance stretches beyond CML to other types of cancers. In the present study, we analyzed PSMD1 and PSMD3 mRNA and protein expression in cancerous tissue versus normal controls using data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), comparing expression with overall survival. Altogether, our data suggest that PSMD1 and PSMD3 may be novel putative targets for cancer prognosis and therapy that are worthy of future investigation.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Complejo de la Endopetidasa Proteasomal/metabolismo , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Pronóstico , Complejo de la Endopetidasa Proteasomal/genética , Tasa de SupervivenciaRESUMEN
Acute myeloid leukemia (AML) is a heterogeneous disease with a poor prognosis and remarkable resistance to chemotherapeutic agents. Understanding resistance mechanisms against currently available drugs helps to recognize the therapeutic obstacles. Various mechanisms of resistance to chemotherapy or targeted inhibitors have been described for AML cells, including a role for the bone marrow niche in both the initiation and persistence of the disease, and in drug resistance of the leukemic stem cell (LSC) population. The BM niche supports LSC survival through direct and indirect interactions among the stromal cells, hematopoietic stem/progenitor cells, and leukemic cells. Additionally, the BM niche mediates changes in metabolic and signal pathway activation due to the acquisition of new mutations or selection and expansion of a minor clone. This review briefly discusses the role of the BM microenvironment and metabolic pathways in resistance to therapy, as discovered through AML clinical studies or cell line and animal models.
Asunto(s)
Médula Ósea/patología , Resistencia a Antineoplásicos , Leucemia Mieloide Aguda/patología , Microambiente Tumoral , Animales , Humanos , Inmunofenotipificación , Leucemia Mieloide Aguda/terapia , Redes y Vías MetabólicasRESUMEN
Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 have revolutionized therapy for chronic myeloid leukemia (CML), paving the way for clinical development in other diseases. Despite success, targeting leukemic stem cells and overcoming drug resistance remain challenges for curative cancer therapy. To identify drivers of kinase-independent TKI resistance in CML, we performed genome-wide expression analyses on TKI-resistant versus sensitive CML cell lines, revealing a nuclear factor-kappa B (NF-κB) expression signature. Nucleocytoplasmic fractionation and luciferase reporter assays confirmed increased NF-κB activity in the nucleus of TKI-resistant versus sensitive CML cell lines and CD34+ patient samples. Two genes that were upregulated in TKI-resistant CML cells were proteasome 26S subunit, non-ATPases 1 (PSMD1) and 3 (PSMD3), both members of the 19S regulatory complex in the 26S proteasome. PSMD1 and PSMD3 were also identified as survival-critical genes in a published small hairpin RNA library screen of TKI resistance. We observed markedly higher levels of PSMD1 and PSMD3 mRNA in CML patients who had progressed to the blast phase compared with the chronic phase of the disease. Knockdown of PSMD1 or PSMD3 protein correlated with reduced survival and increased apoptosis in CML cells, but not in normal cord blood CD34+ progenitors. Luciferase reporter assays and immunoblot analyses demonstrated that PSMD1 and PSMD3 promote NF-κB protein expression in CML, and that signal transducer and activator of transcription 3 (STAT3) further activates NF-κB in scenarios of TKI resistance. Our data identify NF-κB as a transcriptional driver in TKI resistance, and implicate PSMD1 and PSMD3 as plausible therapeutic targets worthy of future investigation in CML and possibly other malignancies.