MIR135A1 (microRNA 135a-1)

Review on MIR135A1, with data on DNA/RNA and where the gene is implicated

PiwiRNA-651 as marker of treatment response and survival in classical Hodgkin lymphoma.

PiwiRNAs, small non-coding RNAs processed by Piwi proteins, are involved in maintaining genome stability in germline cells. Recently, piwiRNA expression has been identified in some tumors. We have examined the potential reactivation of the Piwi/piwiRNA pathway in classical Hodgkin lymphoma (cHL). We found that Piwi proteins and three selected piwiRNAs, including piR-651, were expressed in cHL patients and cell lines, indicating that the Piwi/piwiRNA pathway is active in cHL. Interestingly, low levels of piR-651 were associated with lack of complete response to first-line treatment, as well as shorter disease-free and overall survival in a cohort of 94 cHL patients. At diagnosis, piR-651 was underexpressed in cHL serum samples compared to healthy controls, while after complete remission, piR-651 levels increased to levels similar to healthy controls. This is the first evidence that piwiRNAs are active in tumor and serum samples and impact prognosis in cHL

Risk factors for mortality in patients with acute leukemia and bloodstream infections in the era of multiresistance

Objectives: We assess the epidemiology and risk factors for mortality of bloodstream infection (BSI) in patients with acute leukemia (AL). Methods: Prospectively collected data of a cohort study from July 2004 to February 2016. Multivariate analyses were performed. Results: 589 episodes of BSI were documented in 357 AL patients, 55% caused by gram-positive bacteria (coagulase-negative staphylococci 35.7%, Enterococcus spp 10.8%) and 43.5% by gram-negative bacteria (E. coli 21%, PA 12%). We identified 110 (18.7%) multidrug-resistant (MDR) microorganisms, especially MDR-Pseudomonas aeruginosa (7%) and extended-spectrum beta-lactamase producing Enterobacteriaceae (7%). The 30-day mortality was 14.8%. Age (OR 3.1; 95% CI 1.7–5.7); chronic lung disease (4.8; 1.1–21.8); fatal prognosis according to McCabe index (13.9; 6.4–30.3); shock (3.8; 1.9–7.7); pulmonary infection (3.6; 1.3–9.9); and MDR-PA infections with inappropriate treatment (12.8; 4.1–40.5) were related to mortality. MDR-PA BSI was associated to prior antipseudomonal cephalosporin use (9.31; 4.38–19.79); current use of betalactams (2.01; 1.01–4.3); shock (2.63; 1.03–6.7) and pulmonary source of infection (9.6; 3.4–27.21). Conclusions: MDR organisms were commonly isolated in BSI in AL. Inappropriate empiric antibiotic treatment for MDR-PA is the primary factor related to mortality that can be changed. New treatment strategies to improve the coverage of MDR-PA BSI should be considered in those patients with risk factors for this infection

XIAP inhibitors induce differentiation and impair clonogenic capacity of acute myeloid leukemia stem cells.

Acute myeloid leukemia (AML) is a neoplasia characterized by the rapid expansion of immature myeloid blasts in the bone marrow, and marked by poor prognosis and frequent relapse. As such, new therapeutic approaches are required for remission induction and prevention of relapse. Due to the higher chemotherapy sensitivity and limited life span of more differentiated AML blasts, differentiation-based therapies are a promising therapeutic approach. Based on public available gene expression profiles, a myeloid-specific differentiation-associated gene expression pattern was defined as the therapeutic target. A XIAP inhibitor (Dequalinium chloride, DQA) was identified in an in silico screening searching for small molecules that induce similar gene expression regulation. Treatment with DQA, similarly to Embelin (another XIAP inhibitor), induced cytotoxicity and differentiation in AML. XIAP inhibition differentially impaired cell viability of the most primitive AML blasts and reduced clonogenic capacity of AML cells, sparing healthy mature blood and hematopoietic stem cells. Taken together, these results suggest that XIAP constitutes a potential target for AML treatment and support the evaluation of XIAP inhibitors in clinical trials

The expression level of BAALC-associated microRNA miR-3151 is an independent prognostic factor in younger patients with cytogenetic intermediate-risk acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous disease whose prognosis is mainly related to the biological risk conferred by cytogenetics and molecular profiling. In elderly patients (>= 60 years) with normal karyotype AML miR-3151 have been identified as a prognostic factor. However, miR-3151 prognostic value has not been examined in younger AML patients. In the present work, we have studied miR-3151 alone and in combination with BAALC, its host gene, in a cohort of 181 younger intermediate-risk AML (IR-AML) patients. Patients with higher expression of miR-3151 had shorter overall survival (P = 0.0025), shorter leukemia-free survival (P = 0.026) and higher cumulative incidence of relapse (P = 0.082). Moreover, in the multivariate analysis miR-3151 emerged as independent prognostic marker in both the overall series and within the unfavorable molecular prognostic category. Interestingly, the combined determination of both miR-3151 and BAALC improved this prognostic stratification, with patients with low levels of both parameters showing a better outcome compared with those patients harboring increased levels of one or both markers (P = 0.003). In addition, we studied the microRNA expression profile associated with miR-3151 identifying a six-microRNA signature. In conclusion, the analysis of miR-3151 and BAALC expression may well contribute to an improved prognostic stratification of younger patients with IR-AML

The lincRNA HOTAIRM1, located in the HOXA genomic region, is expressed in acute myeloid leukemia, impacts prognosis in patients in the intermediate-risk cytogenetic category, and is associated with a distinctive microRNA signature

Long non-coding RNAs (lncRNAs) are deregulated in several tumors, although their role in acute myeloid leukemia (AML) is mostly unknown.We have examined the expression of the lncRNA HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) in 241 AML patients. We have correlated HOTAIRM1 expression with a miRNA expression profile. We have also analyzed the prognostic value of HOTAIRM1 expression in 215 intermediate-risk AML (IR-AML) patients.The lowest expression level was observed in acute promyelocytic leukemia (P < 0.001) and the highest in t(6;9) AML (P = 0.005). In 215 IR-AML patients, high HOTAIRM1 expression was independently associated with shorter overall survival (OR:2.04;P = 0.001), shorter leukemia-free survival (OR:2.56; P < 0.001) and a higher cumulative incidence of relapse (OR:1.67; P = 0.046). Moreover, HOTAIRM1 maintained its independent prognostic value within the favorable molecular subgroup (OR: 3.43; P = 0.009). Interestingly, HOTAIRM1 was overexpressed in NPM1-mutated AML (P < 0.001) and within this group retained its prognostic value (OR: 2.21; P = 0.01). Moreover, HOTAIRM1 expression was associated with a specific 33-microRNA signature that included miR-196b (P < 0.001). miR-196b is located in the HOX genomic region and has previously been reported to have an independent prognostic value in AML. miR-196b and HOTAIRM1 in combination as a prognostic factor can classify patients as high-, intermediate-, or low-risk (5-year OS: 24% vs 42% vs 70%; P = 0.004).Determination of HOTAIRM1 level at diagnosis provided relevant prognostic information in IR-AML and allowed refinement of risk stratification based on common molecular markers. The prognostic information provided by HOTAIRM1 was strengthened when combined with miR-196b expression. Furthermore, HOTAIRM1 correlated with a 33-miRNA signature

Factors associated with the clinical outcome of patients with relapsed/refractory CD19+acute lymphoblastic leukemia treated with ARI-0001 CART19-cell therapy

The prognosis of patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) remains poor, particularly for those relapsing after allogeneic hema-topoietic cell transplantation (alloHCT). Novel agents such as inotuzumab ozogamicin or blinatumomab achieve increased response rates, but these are generally transient unless followed by alloHCT. Chimeric antigen receptors (CAR) targeting CD19 have shown promising results in R/R ALL, and one of these products (tisagenlecleucel) has been approved for the treatment of patients with R/R ALL up to 25 years of age

Estudio del patrón de expresión de microRNAs en subtipos de leucemia aguda mieloblástica (LAM) poco frecuentes y análisis del valor pronóstico de microRNAas en LAM de riesgo citogenético intermedio

[spa] Estudios previos han demostrado que los miRNAs juegan un papel muy importante en infinidad de procesos celulares, y son imprescindibles para la correcta homeostasis celular. Su desregulación ha sido ampliamente descrita en cáncer. En este sentido algunos estudios han demostrado que la expresión de miRNAs puede definir entidades de forma más precisa que el estudio de expresión mediante microarrays de miles de RNAs. A partir de este fundamento en esta tesis llevamos a cabo la caracterización del perfil de expresión de miRNA en una amplia cohorte de pacientes con LMA diagnosticados y tratados en nuestro centro y en otros centros del grupo cooperativo CETLAM, correspondientes a una amplia diversidad de variedades citogenéticas y moleculares, con un doble objetivo: una mejor caracterización de los mecanismos biológicos subyacentes de algunas variedades biológicas, menos conocidas, y, por otra parte, el análisis del posible valor pronóstico del nivel de expresión de algunos miRNAs expresados en la enfermedad. Así, y como resultado de los estudios de esta tesis, obtuvimos la firma de miRNA distintiva de la LMA t(8;16). Por otra parte, en un segundo estudio, pudimos identificar algunos miRNA cuyo nivel de expresión proporcionaba información pronóstica adicional a las mutaciones de los genes más habitualmente analizados en la categoría de pacientes con riesgo citogenético intermedio. La leucemia mieloide aguda (LMA) con t(8;16)(p11;p13) (LMA t(8;16)) tiene un perfil clínico- biológico característico, pero su patrón de expresión de microRNAs es desconocido. En el presente trabajo hemos analizado 670 miRNAs maduros en 7 pacientes con LMA con t(8;16) y en 113 pacientes con otros subtipos de LMA, así como en tres controles CD34+ de donante sano. El análisis jerárquico de grupos (“Hierarchical cluster analysis”) demostró que todos los pacientes con LMA t(8;16) se agruparon en un grupo (“cluster”) independiente. Asimismo, el análisis supervisado reveló una firma distintiva de 94 miRNAs, la mayoría de los cuales estaban infraexpresados, entre los que se encontraban el miR-21 y el cluster miR-17-92. Con el objetivo de entender porqué miR-21 y el cluster miR-17-92 se encontraban infraexpresados en este subgrupo en comparación con el resto de grupos de LMA, se estudió la expresión de sus factores de transcripción STAT3 y c-Myc respectivamente. El análisis de expresión del RNAm de dos conocidos factores de transcripción de estos miRNAs (STAT3 y c-Myc) mostró una infraexpresión significativa de STAT3 (P=0.04). Por otra parte, el análisis bioinformático mostró que 29 de los miRNAs que estaban infraexpresados podrían estar regulados por metilación. Con el fin de comprobar si estos miRNAs podían estar regulados por metilación, tratamos una muestra de células primarias de LMA t(8;16) con 5-aza-2'-deoxycytidina (5-AZA-dC) y Tricostatin A (TSA) y encontramos que 27 miRNAs se reexpresaron después de dicho tratamiento. Sin embargo, no se encontraron diferencias en el estado de metilación entre las LMA con t(8;16) y los otros subtipos ni en metilación global, ni en metilación de promotores de miRNAs. Finalmente, se correlacionó la expresión de RNAm (de la que disponíamos de un estudio previo: Camós, Esteve et al; Cancer Res 2006) con la expresión de miRNAs para identificar posibles dianas reguladas por los miRNAs de la firma. La correlación entre la expresion de mRNA y la de miRNAs identificó RET como una potencial diana de tres de los miRNAs característicos de esta entidad. Mediante ensayo de Renilla-Luciferas y citometría de flujo tras la transfección con pre-miRNAs se confirmó que RET estaba regulado por los miRNAs de la firma miR-218, miR-128, miR-27b, miR-15a y miR-195. En conclusión, la LMA t(8;16) presenta una firma característica de miRNAs que está regulada parcialmente mediante mecanismos epigenéticos y que tienen como diana el protooncogén RET. La LMA es una enfermedad heterogénea cuyo tratamiento óptimo varía de acuerdo a los factores de riesgo citogenéticos y los marcadores moleculares. Varios estudios han demostrado la importancia pronóstica de los miRNAs en LMA. En este trabajo analizamos en una serie de 238 pacientes con LMA de riesgo citogenético intermedio (LMA-RI) que provienen de 16 instituciones que forman parte del grupo cooperativo CETLAM, la asociación entre la expresión de algunos miRNAs y el pronóstico clínico. En primer mediante el estudio de expresión de 670 miRNAs en un subgrupo de 85 pacientes de LMA-RI que provenían de una sola institución identificamos 10 miRNAs con valor pronóstico. Posteriormente validamos estos 10 miRNAs mediante ensayos individuales en toda la cohorte (n=288) confirmando el impacto pronóstico de 4 miRNAs. Niveles altos de miR-196b y miR-644 se asociaron de manera independiente con una supervivencia acortada y niveles bajos de miR-135a y miR-409-3p se asociaron con un mayor riesgo de recaída. De manera interesante miR-135a y miR-409-3p mantuvieron su valor pronóstico independiente dentro del subgrupo molecular de mal pronóstico (NPM1 no mutado y CEBPA no mutado y/o FLT3-ITD), y miR-644 mantuvo su valor pronóstico en el subgrupo molecular favorable. En conclusión, en el presente trabajo se han identificado 4 miRNAs con valor pronóstico en LMA-RI, y que además añaden información pronóstica adicional a los marcadores moleculares.[eng] MicroRNAs (miRNAs) are small non-coding RNAs (22–24 nucleotides in length) that have an important regulatory role in most biological processes, including development, regulation of cell proliferation and apoptosis, and stem cell self-renewal and differentiation. Moreover, their expression is altered in cancer, where they can function as both oncogenes and tumor suppressor genes. Several studies have shown the importance of microRNA (miRNA) deregulation in AML. Distinctive miRNA profiles have been identified correponding to specific cytogenetic subtypes. From the prognostic standpoint, some studies have identified several miRNAs associated with clinical outcome. Given the relevant regulatory role of miRNAs in hematopoiesis and their deregulated expression in hematological malignancies including AML, we have analyzed miRNAs expression in AML patients and we have performed two main studies. First, we have described a specific miRNA profile of t(8;16) AML subype and second the prognostic value of miRNAs in a large cohort of patients with IR-AML treated within the Spanish cooperative group CETLAM. Acute myeloid leukemia (AML) with t(8;16)(p11;p13) (t(8;16) AML) has unique clinico-biological characteristics, but its microRNA pattern is unknown. We analyzed 670 microRNAs in seven patients with t(8;16) AML and 113 with other AML subtypes. Hierarchical cluster analysis showed that all t(8;16) AML patients grouped in an independent cluster. Supervised analysis revealed a distinctive signature of 94-microRNAs, most of which were downregulated, including miR-21 and cluster miR-17-92. The mRNA expression analysis of two known transcription factors of these microRNAs (STAT3 and c-Myc, respectively) showed significant downregulation of STAT3 (P=0.04). A bioinformatic analysis showed that 29 of the downregulated microRNAs might be regulated by methylation; we treated a t(8;16) AML sample with 5-aza-2'-deoxycytidine (5-AZA-dC) and trichostatin A and found that 27 microRNAs were re-expressed after treatment. However, there was no difference in methylation status between t(8;16) and other AML subtypes, either overall or in the microRNA promoter. Cross-correlation of mRNA and microRNA expression identified RET as a potential target of several microRNAs. A Renilla-luciferase assay and flow cytometry after transfection with pre-microRNAs confirmed that RET is regulated by miR-218, miR-128, miR-27b, miR-15a and miR-195. In conclusion, t(8;16) AML harbors a specific microRNA signature that is partially epigenetically regulated and targets RET proto-oncogene. Acute myeloid leukemia (AML) is a heterogeneous disease, and optimal treatment varies according to cytogenetic risk factors and molecular markers. Several studies have demonstrated the prognostic importance of microRNAs (miRNAs) in AML. Here we report a potential association between miRNA expression and clinical outcome in 238 intermediate-risk cytogenetic AML (IR-AML) patients from 16 institutions in the CETLAM cooperative group. We first profiled 670 miRNAs in a subset of 85 IR-AML patients from a single institution and identified 10 outcome-related miRNAs. We then validated these 10 miRNAs by individual assays in the total cohort and confirmed the prognostic impact of 4 miRNAs. High levels of miR-196b and miR-644 were independently associated with shorter overall survival, and low levels of miR-135a and miR-409-3p with a higher risk of relapse. Interestingly, miR-135a and miR-409-3p maintained their independent prognostic value within the unfavorable molecular subcategory (wild-type NPM1 and CEBPA and/or FLT3-ITD), and miR-644 retained its value within the favorable molecular subcategory. miR-409-3p, miR-135a, miR-196b and mir-644 arose as prognostic markers for IR-AML, both overall and within specific molecular subgroups