NON-COMMUNICABLE DISEASES / Cancer
Research Interests
Lymphoid neoplasms; Chronic Lymphocytic Leukemia, Targeted therapy; Signal transduction; B-cell receptor
Description of Research
The main research interest of the Molecular Hematology Group are B cell malignancies, particularly chronic lymphocytic leukemia (CLL) and diffuse large B cell lymphoma, with the main focus on establishing new cellular and animal models to better understand the molecular mechanisms that drive these diseases and for preclinical assessment of new therapeutic agents.
Most of the current work focuses on CLL, which is the most common type of leukemia among adults. Based on a better understanding of the disease biology, targeted treatments have been developed in recent years that have revolutionized the management of the disease, yet have led to additional research questions. In particular, the role of the various genetic lesions and microenvironmental stimuli in mediating treatment resistance has still not been defined. In addition, the mechanisms through which individual genetic lesions contribute to CLL development and progression are still poorly understood and only a few have been validated as true drivers in animal models. Finally, the relative importance of individual microenvironmental signals in promoting CLL cell growth and survival is still largely unknown.
To address these questions, we recently developed a CRISPR/Cas9-based procedure that allows for rapid and efficient introduction of multiple CLL patient-specific genetic lesions in normal and leukemic murine B cells. We have been using this procedure to generate murine leukemias with the genetic make-up of human CLL and to study the role of selected genetic lesions during CLL development, progression and transformation of CLL into aggressive lymphoma. In addition, we have developed a similar approach to genetically inactivate intracellular pathways that propagate the putative microenvironmental signals in primary murine and human CLL cells and investigate how this will affect the growth of the malignant cells following their transplantation in immunocompetent or immunodeficient mice, respectively. Both approaches are also currently being used to investigate the impact of selected genetic lesions and microenvironmental signals on resistance to treatment with the novel targeted therapies.
Recent Publications
Bonato A, Chakraborty S, Bomben R, Canarutto G, Felician G, Martines C, Zucchetto A, Pozzo F, Vujovikj M, Polesel J, Chiarenza A, Del Principe MI, Del Poeta G, D’Arena G, Marasca R, Tafuri A, Laurenti L, Piazza S, Dimovski AJ, Gattei V, Efremov DG. NFKBIE mutations are selected by the tumor microenvironment and contribute to immune escape in chronic lymphocytic leukemia. Leukemia. 2024; 38(7):1511-1521.
Negara I, Tomuleasa C, Buruiana S, Efremov DG. Molecular Subtypes and the Role of TP53 in Diffuse Large B-Cell Lymphoma and Richter Syndrome. Cancers. 2024; 16(12):2170.
Roessner PM, Seufert I, Chapaprieta V, Jayabalan R, Briesch H, Massoni-Badosa R, Boskovic P, Beckendorff J, Roider T, Arseni L, Coelho M, Chakraborty S, Vaca A, Sivina M, Muckenhuber M, Rodriguez-Rodriguez S, Bonato A, Herbst SA, Zapatka M, Sun C, Kretzmer H, Naake T, Bruch PM, Czernilofsky F, Ten Hacken E, Schneider M, Helm D, Yosifov DY, Kauer J, Danilov AV, Bewarder M, Heyne K, Schneider C, Stilgenbauer S, Wiestner A, Mallm JP, Burger JA, Efremov DG, Lichter P, Dietrich S, Martín-Subero JI, Rippe K, Seiffert M. T-bet suppresses proliferation of malignant B cells in chronic lymphocytic leukemia. Blood. 2024; 144(5):510-524.
Largeot A, Klapp V, Viry E, Gonder S, Fernandez Botana I, Blomme A, Benzarti M, Pierson S, Duculty C, Marttila P, Wierz M, Gargiulo E, Pagano G, An N, El Hachem N, Perez Hermandez D, Chakraborty S, Ysebaert L, François JH, Cortez Clemente SD, Berchem G, Efremov DG, Dittmar G, Szpakowska M, Chevigne A, Nazarov PV, Helleday T, Close P, Meiser J, Stamatopoulos B, Désaubry L, Paggetti J, Moussay E. Inhibition of MYC translation through targeting of the newly identified PHB-eIF4F complex as therapeutic strategy in CLL. Blood. 2023; 141(26):3166-3183.
Martines C, Chakraborty S, Vujovikj M, Gobessi S, Vaisitti T, Deaglio S, Laurenti L, Dimovski AJ, Efremov DG. Macrophage- and BCR- but not TLR-derived signals support the growth of CLL and Richter Syndrome murine models in vivo. Blood. 2022; 140(22):2335-2347.
Chakraborty S, Martines C, Porro F, Fortunati I, Bonato A, Dimishkovska M, Piazza S, Yadav BS, Innocenti I, Fazio R, Vaisitti T, Deaglio S, Zamò A, Dimovski AJ, Laurenti L, Efremov DG. B Cell Receptor signaling and genetic lesions in TP53 and CDKN2A/CDKN2B cooperate in Richter Transformation. Blood, 2021. 138(12):1053-1066.
Group Leader
Dimitar Efremov
ICGEB Trieste, Italy
E-mail: [email protected]
Tel: +39-040-3757212
Group Leader CV
Group Members
Giulia Felician, Research Technician
Esther Sathya Bama Benjamin Prem Kumar, Postdoc
Claudio Martines, Postdoc
Ivan Negara, Postdoc