Banús-Mulet A, Etxabe A, Cornet-Masana JM, Torrente MÁ, Lara-Castillo MC, Palomo L, Nomdedeu M, Díaz-Beyá M, Solé F, Nomdedeu B, Esteve J, Risueño RM
Serotonin receptor type 1B constitutes a therapeutic target for MDS and CMML.
Sci Rep17 Sep 2018, 8(1)13883. Epub 17 Sep 2018
Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are chronic myeloid clonal neoplasms. To date, the only potentially curative therapy for these disorders remains allogeneic hematopoietic progenitor cell transplantation (HCT), although patient eligibility is limited due to high morbimortality associated with this procedure coupled with advanced age of most patients. Dopamine receptors (DRs) and serotonin receptors type 1 (HTR1s) were identified as cancer stem cell therapeutic targets in acute myeloid leukemia. Given their close pathophysiologic relationship, expression of HTR1s and DRs was interrogated in MDS and CMML. Both receptors were differentially expressed in patient samples compared to healthy donors. Treatment with HTR1B antagonists reduced cell viability. HTR1 antagonists showed a synergistic cytotoxic effect with currently approved hypomethylating agents in AML cells. Our results suggest that HTR1B constitutes a novel therapeutic target for MDS and CMML. Due to its druggability, the clinical development of new regimens based on this target is promising.
Benoit YD, Mitchell RR, Risueño RM, Orlando L, Tanasijevic B, Boyd AL, Aslostovar L, Salci KR, Shapovalova Z, Russell J, Eguchi M, Golubeva D, Graham M, Xenocostas A, Trus MR, Foley R, Leber B, Collins TJ, Bhatia M
Sam68 Allows Selective Targeting of Human Cancer Stem Cells.
Cell Chem Biol20 Jul 2017, 24(7)833-844.e9. Epub 22 Jun 2017
Targeting of human cancer stem cells (CSCs) requires the identification of vulnerabilities unique to CSCs versus healthy resident stem cells (SCs). Unfortunately, dysregulated pathways that support transformed CSCs, such as Wnt/β-catenin signaling, are also critical regulators of healthy SCs. Using the ICG-001 and CWP family of small molecules, we reveal Sam68 as a previously unappreciated modulator of Wnt/β-catenin signaling within CSCs. Disruption of CBP-β-catenin interaction via ICG-001/CWP induces the formation of a Sam68-CBP complex in CSCs that alters Wnt signaling toward apoptosis and differentiation induction. Our study identifies Sam68 as a regulator of human CSC vulnerability.
Etxabe A, Lara-Castillo MC, Cornet-Masana JM, Banús-Mulet A, Nomdedeu M, Torrente MA, Pratcorona M, Díaz-Beyá M, Esteve J, Risueño RM
Inhibition of serotonin receptor type 1 in acute myeloid leukemia impairs leukemia stem cell functionality: a promising novel therapeutic target.
Leukemia10 Mar 2017, . Epub 10 Mar 2017
Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous neoplasia with poor outcome, organized as a hierarchy initiated and maintained by a sub-population with differentiation and self-renewal capacities called leukemia stem cells (LSCs). Although currently used chemotherapy is capable of initially reducing the tumor burden producing a complete remission, most patients will ultimately relapse and will succumb to their disease. As such, new therapeutic strategies are needed. AML cells differentially expressed serotonin receptor type 1 (HTR1) compared with healthy blood cells and the most primitive hematopoietic fraction; in fact, HTR1B expression on AML patient samples correlated with clinical outcome. Inhibition of HTR1s activated the apoptosis program, induced differentiation and reduced the clonogenic capacity, while minimal effect was observed on healthy blood cells. In vivo regeneration capacity of primary AML samples was disrupted upon inhibition of HTR1. The self-renewal capacity remaining in AML cells upon in vivo treatment was severely reduced as demonstrated by serial transplantation. Thus, treatment with HTR1 antagonists showed antileukemia effect, especially anti-LSC activity while sparing healthy blood cells. Our results highlight the importance of HTR1 in leukemogenesis and LSC survival and identify this receptor family as a new target for therapy in AML with prognostic value.Leukemia advance online publication, 10 March 2017; doi:10.1038/leu.2017.52.
Cornet-Masana JM, Moreno-Martínez D, Lara-Castillo MC, Nomdedeu M, Etxabe A, Tesi N, Pratcorona M, Esteve J, Risueño RM
Emetine induces chemosensitivity and reduces clonogenicity of acute myeloid leukemia cells.
Oncotarget15 Mar 2016, . Epub 15 Mar 2016
Acute myeloid leukemia (AML) is an hematologic neoplasia characterized by the accumulation of transformed immature myeloid cells in bone marrow. Although the response rate to induction therapy is high, survival rate 5-year after diagnosis is still low, highlighting the necessity of new novel agents. To identify agents with the capability to abolish the self-renewal capacity of AML blasts, an in silico screening was performed to search for small molecules that induce terminal differentiation. Emetine, a hit compound, was validated for its anti-leukemic effect in vitro, ex vivo and in vivo. Emetine, a second-line anti-protozoa drug, differentially reduced cell viability and clonogenic capacity of AML primary patient samples, sparing healthy blood cells. Emetine treatment markedly reduced AML burden in bone marrow of xenotransplanted mice and decreased self-renewal capacity of the remaining engrafted AML cells. Emetine also synergized with commonly used chemotherapeutic agents such as ara-C. At a molecular level, emetine treatment was followed by a reduction in HIF-1α protein levels. This study validated the anti-leukemiceffect of emetine in AML cell lines, a group of diverse AML primary samples, and in a human AML-transplanted murine model, sparing healthy blood cells. The selective anti-leukemic effect of emetine together with the safety of the dose range required to exert this effect support the development of this agent in clinical practice.
Lara-Castillo MC, Cornet-Masana JM, Etxabe A, Banús-Mulet A, Torrente MÁ, Nomdedeu M, Díaz-Beyá M, Esteve J, Risueño RM
Repositioning of bromocriptine for treatment of acute myeloid leukemia.
J Transl Med2016, 14261. Epub 7 Sep 2016
Treatment for acute myeloid leukemia (AML) has not significantly changed in the last decades and new therapeutic approaches are needed to achieve prolonged survival rates. Leukemia stem cells (LSC) are responsible for the initiation and maintenance of AML due to their stem-cell properties. Differentiation therapies aim to abrogate the self-renewal capacity and diminish blast lifespan.
Díaz-Beyá M, Brunet S, Nomdedéu J, Pratcorona M, Cordeiro A, Gallardo D, Escoda L, Tormo M, Heras I, Ribera JM, Duarte R, de Llano MP, Bargay J, Sampol A, Nomdedeu M, Risueño RM, Hoyos M, Sierra J, Monzo M, Navarro A, Esteve J
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.
Oncotarget13 Oct 2015, 6(31)31613-27.
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.
Díaz-Beyá M, Brunet S, Nomdedéu J, Cordeiro A, Tormo M, Escoda L, Ribera JM, Arnan M, Heras I, Gallardo D, Bargay J, Queipo de Llano MP, Salamero O, Martí JM, Sampol A, Pedro C, Hoyos M, Pratcorona M, Castellano JJ, Nomdedeu M, Risueño RM, Sierra J, Monzó M, Navarro A, Esteve J
The expression level of BAALC-associated microRNA miR-3151 is an independent prognostic factor in younger patients with cytogenetic intermediate-risk acute myeloid leukemia.
Blood Cancer J2015, 5e352. Epub 2 Oct 2015
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.
Nomdedeu M, Lara-Castillo MC, Etxabe A, Cornet-Masana JM, Pratcorona M, Díaz-Beyá M, Calvo X, Rozman M, Costa D, Esteve J, Risueño RM
Treatment with G-CSF reduces acute myeloid leukemia blast viability in the presence of bone marrow stroma.
Cancer Cell Int.2015, 15122. Epub 21 Dec 2015
The resulting clinical impact of the combined use of G-CSF with chemotherapy as a chemosensitizing strategy for treatment of acute myeloid leukemia (AML) patients is still controversial. In this study, the effect of ex vivo treatment with G-CSF on AML primary blasts was studied.
Calvo X, Nomdedeu M, Navarro A, Tejero R, Costa D, Muñoz C, Pereira A, Peña O, Risueño RM, Monzó M, Esteve J, Nomdedeu B
High levels of global DNA methylation are an independent adverse prognostic factor in a series of 90 patients with de novo myelodysplastic syndrome.
Leuk. Res.Aug 2014, 38(8)874-81. Epub 12 May 2014
The prognostic impact of global DNA methylation and hydroxymethylation was assessed in 90 patients with de novo myelodysplastic syndrome (MDS). DNA was isolated from bone marrow samples obtained at diagnosis and global methylation and hydroxymethylation were determined by ELISA. Patients with a percentage of methylated DNA above 2.73% had a shorter overall survival than those with lower levels (P=0.018) and presented a negative trend in terms of leukemia-free survival (P=0.084), that was statistically significant after censoring 9 patients that received disease-modifying treatments both in univariate and multivariate analyses. Similarly, the low-risk MDS patients defined by the IPSS, WPSS and IPSS-R with 5-mC percentage in total DNA above 2.73% had a shorter overall survival (P=0.032; P=0.023; P=0.031). No cut-off value for the 5-hydroxymethylcytosine percentage with statistical significance for overall or leukemia-free survival was obtained. This study suggests that global DNA methylation predicts overall survival in myelodysplastic syndromes.