Leukemia Stem Cell Group

  • Risueño group
+34 932 275 400
Clínic-UB

Josep Carreras Leukaemia Research Institute
Hospital Clínic Barcelona. Universitat de Barcelona.
Centre Esther Koplowitz
c/ Rosselló, 149-153, 2 pl
08036 Barcelona (Spain)

Fax: (+34) 93 312 9407

 

Summary

Acute myeloid leukemia (AML) is a blood cancer, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with normal hematopoiesis. Although, remission rates with standard induction chemotherapy in patients with AML range from 50-85% the majority of patients will relapse and succumb to the disease within 5 years. As such, survival rates for the majority of patients with AML have not dramatically changed over the last decades and new therapeutic approaches are required for remission induction and prevention of relapse. Leukemia stem cells (LSC) are the cell population within the tumor thought to be responsible for the initiation, maintenance and relapse of the leukemia. Therefore, development of specific therapies targeted at LSCs holds hope for improvement of survival and quality of life of leukemia patients.

Research

Acute myeloid leukemia (AML) is a neoplasia characterized by the rapid expansion of immature myeloid blasts in the bone marrow. The course of the disease is marked by poor prognosis, frequent relapse, and high disease-related mortality. As such, new therapeutic approaches are required for remission induction and prevention of relapse. The difficulty in treating AML is thought to arise from a chemoresistant subpopulation of leukemia stem cells (LSCs) that are capable of maintaining and reinitiating disease. Our research program focuses on the development of therapeutic strategies for targeting LSCs.

New therapeutic targets for leukemia stem cells

Due to the higher chemotherapy sensitivity and limited life span of more differentiated AML blasts, differentiation-based combinatorial therapies that eliminate blasts are a promising therapeutic approach. As LSCs display the highest differentiation capacity due to the tightly regulated balance between self-renewal and differentiation, a therapy that favours differentiation would potentially also exhaust this population and eradicate the cells responsible for the initiation and maintenance of AML. An in silico screening was performed to search for already FDA-approved drugs that may induce LSC differentiation and spare healthy hematopoietic stem cells (HSCs). The drugs identified are been validated in vitro and ex vivo. The mechanism of action of these drugs on AML-LSCs will be characterized and their potential clinical use for leukemia will be studied. Additionally, new therapeutic targets from the signalling pathway identified will be evaluated. While describing the signalling pathway implicated in the block of differentiation will increase the knowledge of the biology that drives the leukemogenesis process, searching for new drugs that disrupt this intracellular signalling will allow new biomarkers and therapeutic targets to be defined for AML, and especially LSCs.

Oncogenic pathways responsible for leukemia transformation and response to therapy

Improving the knowledge of the molecular mechanisms responsible for human blood cell transformation is essential for a better understanding of leukemia pathogenesis and to guide rational development of patient-based therapies. Working in close collaboration with the AML Clinical Research Group (Hospital Clínic de Barcelona), we aim to understand how LSCs are affected in patients undergoing conventional therapy, in terms of survival and function to help design better patients-specific therapies. Additionally, we are studying the mechanisms underlying oncogenics events that lead the transformation from Myelodysplasic Syndrome (MDS) to AML.

Collaborations

Dr. Jordi Esteve, Hematology Department, Hospital Clínic. Barcelona, Spain
Dr. Joaquín Martínez-López, Hematology Department, Hospital Doce de Octubre, Madrid, Spain
Dr. Mariano Monzó. Faculty of Medicine, University of Barcelona. Barcelona, Spain
Dr. Romain Quidant, ICFO- The Institute of Photonics Sciences, Barcelona, Spain
Dr. Benet Nomdedeu. Hematology Department. Hospital Clínic. Barcelona, Spain

People

Selected publications

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.

Leukemia 10 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.
Més informació
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 Med 2016, 14 261. Epub 7 Set 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.
Més informació
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.

Oncotarget 15 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.
Més informació
Moreno-Martínez D, Nomdedeu M, Lara-Castillo MC, Etxabe A, Pratcorona M, Tesi N, Díaz-Beyá M, Rozman M, Montserrat E, Urbano-Ispizua A, Esteve J, Risueño RM

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

Oncotarget 30 Jun 2014, 5 (12) 4337-46.
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.
Més informació
Sachlos E, Risueño RM, Laronde S, Shapovalova Z, Lee JH, Russell J, Malig M, McNicol JD, Fiebig-Comyn A, Graham M, Levadoux-Martin M, Lee JB, Giacomelli AO, Hassell JA, Fischer-Russell D, Trus MR, Foley R, Leber B, Xenocostas A, Brown ED, Collins TJ, Bhatia M

Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells.

Cell 8 Jun 2012, 149 (6) 1284-97. Epub 24 Mai 2012
Selective targeting of cancer stem cells (CSCs) offers promise for a new generation of therapeutics. However, assays for both human CSCs and normal stem cells that are amenable to robust biological screens are limited. Using a discovery platform that reveals differences between neoplastic and normal human pluripotent stem cells (hPSC), we identify small molecules from libraries of known compounds that induce differentiation to overcome neoplastic self-renewal. Surprisingly, thioridazine, an antipsychotic drug, selectively targets the neoplastic cells, and impairs human somatic CSCs capable of in vivo leukemic disease initiation while having no effect on normal blood SCs. The drug antagonizes dopamine receptors that are expressed on CSCs and on breast cancer cells as well. These results suggest that dopamine receptors may serve as a biomarker for diverse malignancies, demonstrate the utility of using neoplastic hPSCs for identifying CSC-targeting drugs, and provide support for the use of differentiation as a therapeutic strategy.
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Current projects

Estudio de la Implicación de los Receptores de Serotonina en los Procesos de Transformación Leucémica

Responsable:Ruth Muñoz Risueño
Codi:SAF2015-66721-P
Financiadors:
Data d'inici:01/01/2016
Data de finalització:31/12/2019

Nuevo tratamiento para la leucemia mieloide aguda y los síndromes mielodisplásicos

Responsable:Ruth Muñoz Risueño
Codi:RTC-2016-5205-1
Financiadors:
Data d'inici:01/01/2016
Data de finalització:31/12/2019

Development of new therapeutic approaches for leukemia

Responsable:Ruth Muñoz Risueño
Financiadors:
Data d'inici:01/01/2017
Data de finalització:31/12/2018

Nuevas dianas terapéuticas en leucemia mieloide aguda

Responsable:Ruth Muñoz Risueño
Financiadors:
Data d'inici:01/01/2015
Data de finalització:31/12/2017

Previous projects

Nuevos fármacos contra células madre leucémicas. Ensayos preclínicos in vivo. AECC-JP Barcelona

Responsable:Ruth Muñoz Risueño
Codi:AECC-JP
Financiadors:
Data d'inici:01/01/2014
Data de finalització:30/05/2015

Búsqueda de nuevas dianas terapéuticas en leucemia mieloide aguda

Responsable:Ruth Muñoz Risueño
Codi:SAF2012-34352
Financiadors:
Data d'inici:01/01/2013
Data de finalització:31/12/2015