Leukemia and Immuno-Oncology

  • Grup Laura Belver
+34 935 572 800
Campus ICO-Germans Trias i Pujol
ICO - Germans Trias i Pujol

Josep Carreras Leukaemia Research Institute 
Can Ruti Campus  - Ctra de Can Ruti, Camí de les Escoles s/n
08916 Badalona, Barcelona



Our research is focused on the study of the molecular mechanisms driving leukemogenesis and on the identification of new therapeutic targets that can potentially translate into novel strategies for the treatment of leukemia patients. More specifically, one of our main interests is to identify and characterize non-coding genetic alterations that can induce aberrant enhancer activity, and function as drivers of leukemia transformation or contribute to leukemia progression through other means.

In addition, we are interested on the specific role of the immune system in developing antitumor responses. In particular, we will focus on the molecular characterization of the beneficial and deleterious responses induced by the use of immune-checkpoint inhibitors for the treatment of different tumor types.


1) Molecular pathways and targeted therapies in Juvenile Myelomonocytic Leukemia (JMML)

Juvenile myelomonocytic leukemia (JMML) is a pediatric myeloproliferative disorder characterized by the constitutive activation of the RAS signaling pathway. Most of the patients with JMML experience an aggressive clinical course of the disease and require hematopoietic stem cell transplantation (HSCT), which is currently the only therapeutic option to achieve long-term remission. However, this treatment entails a significant risk of transplant-related mortality in these patients and still, the overall survival at five years remains at 64%. In spite of the progresses made in the last years on the genetic and epigenetic characterization of JMML, this disease is still a clinical challenge due to its heterogeneity, difficult diagnosis, poor prognosis and the lack of alternative treatment options other than HSCT.

Our overarching goal is to integrate different methods in epigenetics, systems biology, functional genomics and biochemistry to address critical questions about the origin and progression of JMML, and to identify new therapeutic targets for the treatment of this disease. The specific aims of our research are: 

  • To establish a JMML working group in Spain and create a centralized JMML sample repository.
  • To develop a comprehensive molecular analysis of JMML patients to define accurate diagnostic and stratification criteria and identify new potential therapeutic targets.
  • To develop molecular- and cell-based therapies for the treatment of JMML.

2) Molecular mechanisms driving immune checkpoint inhibitor (ICI) antitumoral and toxic effects

The immune system is regulated by a number of inhibitory pathways that are essential to maintain self-tolerance and prevent immune-mediated tissue damage. During tumor progression, cancer cells develop strategies that allow them to hijack these immunological checkpoints in order to evade immune attack. Therapies based on immune checkpoint inhibitors (ICIs) targeting immune-escape mechanisms have been a major breakthrough for cancer treatment and are currently being used in a broad range of tumor types. However, immune deregulation in the context of ICI therapies is frequently associated with the development of immune-related adverse events (irAEs), a wide espectrum of autoimmune toxicities that in some cases result in premature termination of the therapy and that can be fatal in a low but significant proportion of the patients.

Here, we will integrate different methods in immunology, genetics, molecular biology and functional genomics to dissect the mechanisms that control therapeutic and adverse ICI-driven immune responses. Our specific aims are: 

  • To characterize the distinct molecular cues that govern anti-tumor and autoimmune responses induced by ICI immunotherapy.
  • To identify and validate immune modulators as therapeutic targets to maximize the antitumor activity of ICIs while minimizing their acute and long term toxic side effects.


2019 Early Career International Award
        (European School of Haematology)

2019 Acute Leukemia Forum Young Investigator Award  

2018 ASH Abstract Achievement Award
        (American Society of Hematology)

2011 VI Biogen-Idec Award for Young Investigators
        (Biogen-Idec Foundation)


Laura BelverLaura BelverGroup Leader

Selected publications

Belver, L., Yang, A.Y., Albero, R., Herranz, D., Brundu, F.G., Quinn, S.A., Pérez-Durán, P., Álvarez, S., Gianni, F., Rashkovan, M., Gurung, D., Rocha, P.P., Raviram, R., Reglero, C., Cortés, J.R., Cooke, A., Wendorff, A., Cordó, V., Meijerink, J., Rabadán, R., and Ferrando, A.A

Gata3-controlled nucleosome eviction drives Myc enhancer activity in T-cell development and leukemia

Cancer Discov. 2019; 9, 1774-1791. , .
Long-range enhancers govern the temporal and spatial control of gene expression; however, the mechanisms that regulate enhancer activity during normal and malignant development remain poorly understood. Here, we demonstrate a role for aberrant chromatin accessibility in the regulation of MYC expression in T-cell lymphoblastic leukemia (T-ALL). Central to this process, the NOTCH1-MYC enhancer (N-Me), a long-range T cell–specific MYC enhancer, shows dynamic changes in chromatin accessibility during T-cell specification and maturation and an aberrant high degree of chromatin accessibility in mouse and human T-ALL cells. Mechanistically, we demonstrate that GATA3-driven nucleosome eviction dynamically modulates N-Me enhancer activity and is strictly required for NOTCH1-induced T-ALL initiation and maintenance. These results directly implicate aberrant regulation of chromatin accessibility at oncogenic enhancers as a mechanism of leukemic transformation.
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Cortés, J.R., Ambesi-Impiombato, A., Couronné, L., Quinn, S.A., Kim, C.S., da Silva Almeida, A.C., West, Z., Belver, L., Sánchez-Martín, M., Scourzic, L., Bhagat, G., Bernard, O.A., Ferrando, A.A., and Palomero, T

RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis

Cancer Cell. 2018; 33, 259-273. , .
Angioimmunoblastic T cell lymphoma (AITL) is an aggressive tumor derived from malignant transformation of T follicular helper (Tfh) cells. AITL is characterized by loss-of-function mutations in Ten-Eleven Translocation 2 (TET2) epigenetic tumor suppressor and a highly recurrent mutation (p.Gly17Val) in the RHOA small GTPase. Yet, the specific role of RHOA G17V in AITL remains unknown. Expression of Rhoa G17V in CD4+ T cells induces Tfh cell specification; increased proliferation associated with inducible co-stimulator (ICOS) upregulation and increased phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase signaling. Moreover, RHOA G17V expression together with Tet2 loss resulted in development of AITL in mice. Importantly, Tet2-/-RHOA G17V tumor proliferation in vivo can be inhibited by ICOS/PI3K-specific blockade, supporting a driving role for ICOS signaling in Tfh cell transformation.
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Belver, L., Ferrando, A.A

The genetics and mechanisms of T-cell acute lymphoblastic leukemia

Nat Rev Cancer. 2016; 16, 494-507. , .
T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive haematological malignancy derived from early T cell progenitors. In recent years genomic and transcriptomic studies have uncovered major oncogenic and tumour suppressor pathways involved in T-ALL transformation and identified distinct biological groups associated with prognosis. An increased understanding of T-ALL biology has already translated into new prognostic biomarkers and improved animal models of leukaemia and has opened opportunities for the development of targeted therapies for the treatment of this disease. In this Review we examine our current understanding of the molecular mechanisms of T-ALL and recent developments in the translation of these results to the clinic.
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Puente, X.S., Beà, S., Valdés-Mas, R., Villamor, N., Gutiérrez-Abril, J., Martín-Subero, J.I., Munar, M., Rubio-Pérez, C., Jares, P., Aymerich, M., Baumann, T., Beekman, R., Belver, L., Carrio, A., Castellano, G., Clot, G., Colado, E., Colomer, D., Costa, D., Delgado, J., Enjuanes, A., Estivill, X., Ferrando, A.A., Gelpí, J.L., González, B., González, S., González, M., Gut, M., Hernández-Rivas, J.M., López-Guerra, M., Martín-García, D., Navarro, A., Nicolás, P., Orozco, M., Payer, Á.R., Pinyol, M., Pisano, D.G., Puente, D.A., Queirós, A.C., Quesada, V., Romeo-Casabona, C.M., Royo, C., Royo, R., Rozman, M., Russiñol, N., Salaverría, I., Stamatopoulos, K., Stunnenberg, H.G., Tamborero, D., Terol, M.J., Valencia, A., López-Bigas, N., Torrents, D., Gut, I., López-Guillermo, A., López-Otín, C., and Campo, E

Non-coding recurrent mutations in chronic lymphocytic leukaemia

Nature. 2015; 526, 519-524 , .
Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3' region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.
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Herranz, D., Ambesi-Impiombato, A., Sudderth, J., Sánchez-Martín, M, Belver, L., Tosello, V., Xu, L., Wendorff, A.A., Castillo, M., Haydu, J.E., Márquez, J., Matés, J.M., Kung, A.L., Rayport, S., Cordon-Cardo, C., DeBerardinis, R.J., and Ferrando, A.A

Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia

Nat Med. 2015; 21, 1182-1189. , .
Activating mutations in NOTCH1 are common in T cell acute lymphoblastic leukemia (T-ALL). Here we identify glutaminolysis as a critical pathway for leukemia cell growth downstream of NOTCH1 and a key determinant of the response to anti-NOTCH1 therapies in vivo. Mechanistically, inhibition of NOTCH1 signaling in T-ALL induces a metabolic shutdown, with prominent inhibition of glutaminolysis and triggers autophagy as a salvage pathway supporting leukemia cell metabolism. Consequently, inhibition of glutaminolysis and inhibition of autophagy strongly and synergistically enhance the antileukemic effects of anti-NOTCH1 therapy in mice harboring T-ALL. Moreover, we demonstrate that Pten loss upregulates glycolysis and consequently rescues leukemic cell metabolism, thereby abrogating the antileukemic effects of NOTCH1 inhibition. Overall, these results identify glutaminolysis as a major node in cancer metabolism controlled by NOTCH1 and as therapeutic target for the treatment of T-ALL.
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