Which are the mechanisms regulating malignant B lymphocyte growth, fitness and resilience to cytotoxic agents?

Non-Hodgkin lymphomas (NHL) and multiple myeloma (MM) are B-cell derived tumours and represent the vast majority of hematologic cancers, in many instances still incurable. We aim at defining the determinants of intrinsic and extrinsic growth signals for NHL and MM cells. Our laboratory is particularly interested in identifying novel regulators of cellular fitness and stress resistance to be targeted in novel therapeutic approaches for NHL and MM.

NHL and MM cell growth and proliferation implies a continuous exposition to different kinds of stresses, as for instance the oxidative, replicative, proteotoxic and DNA damage-related harmful burdens. The precise mechanisms regulating NHL and MM cell capability of coping with such damaging noxae are largely unknown. Since B cells have physiological mechanisms regulating immunoglobulin gene rearrangements (class switch recombination and somatic hypermutation) handling DNA double strand breaks and, at the plasmacellular differentiation stage, coping with the protetoxic and oxidative noxious load, one possible way the malignant B cell counterparts may survive to different stresses is through an over-exploitation of these pathways. Therefore - while essential for malignant B cell survival – these stress-managing cascades also represent exquisite points of therapeutic vulnerability. By using multifaceted experimental approaches, utilizing NHL and MM cell lines, primary cells from patients, tissue sections, mouse models, genomic, transcriptomic and proteomic tools, we demonstrated that the family of serine-threonine kinases CK1 and CK2 are important modulators of the activation of the NF-B, PI3K/AKT and JAK/STAT signaling pathways in NHL and MM and are fundamental to sustain the response to endoplasmic reticulum (ER)/proteotoxic stress. Our loss-of-function models of CK1 and CK2 in mouse B lymphocytes demonstrate the essential role of these kinases and are fundamental tools to study their function in B cell physiology and pathobiology. We aim to explore 1) the physiological role of CK1 and CK2 in hemo-lymphopoiesis; 2) the exact function of CK1 and CK2 in the transmission of signals from the B-cell receptor to the nucleus in malignant lymphoma; 3) the role of CK1 in autophagy in NHL and MM; 4) the role of CK2 in the ER stress and in the DNA damage response in NHL and MM.

FRANCESCO PIAZZA

  • • MD, University of Padova, Italy (1995)
  • Board in Medical Oncology, University of Padova, Italy (2000)
  • Postdoc: Memorial Sloan-Kettering Cancer Center, New York, USA (1999-2003)
  • Assistant Professor of Hematology, Dept. of Medicine, University of Padua (since 2008)
  • Group leader: Hematological Malignancies, Lymphoma and Myeloma Pathobiology, Venetian Institute of Molecular Medicine, Padua, Italy (since 2013)

Selected Awards

  • 2004: Brian D. Novis Junior Award, International Myeloma Foundation (USA)
  • 2006: “Guido Berlucchi” Award for young oncologists, Italy