Is a Protective Microenvironment the “Achille’s Heel” in Chronic Lymphocytic Leukemia?
Pp. 3-41 (39)
Paolo Giannoni and Daniela de Totero
Chronic lymphocytic leukemia (CLL) is a B cell malignancy characterized
by the accumulation of mature monoclonal CD5-positive B cells in the blood, secondary
lymphoid tissues and marrow. Despite much advancement in therapy during the last
decade, CLL is still considered an incurable disease. The combination of different drugs
such as fludarabine, cyclophosphamide and rituximab (FCR) have led to improved
progression free-survival and overall survival but only 45% of patients achieve a
complete remission and nearly all patients eventually relapse.
Chronic lymphocytic leukemic cells are characterized by an apparent longevity in vivo
which is lost when they are cultured in vitro. This observation suggests that cellular
interactions and factors provided by the microenvironment are essential to cell survival and
may protect leukemic cells from the cytotoxicity of conventional therapies. Moreover the
infiltration of CLL cells in lymphoid tissue and in bone marrow is a key element in disease
pathogenesis and correlates with clinical stage. Increasing emphasis is now placed on
understanding the leukemic/stromal cells cross-talk to identify signals supporting disease
progression and to explore novel therapies targeting the microenvironment. This review
will focus on critical cellular and molecular pathways of CLL-microenvironment
interactions: in vitro and in vivo models for studying the CLL microenvironment will be
discussed and new strategies that are being evaluated to disrupt protective signals that
support expansion of the neoplastic B cell clone will be described.
Chronic lymphocytic leukemia, cytokines, growth factors,
microenvironment, bone marrow, lymph-nodes.
Transfer Gene Laboratory, IRCCS San Martino Hospital- National Institute for Cancer Research (IST), Largo R. Benzi, 10; 16132, Genoa; Italy