Our Research Objectives

Mechanisms regulating differentiation and survival of cells in health and disease

B cells: In normal individuals, the pool of peripheral lymphocytes is constant in size. The control of lymphoid homeostasis is the result of a very fine balance between lymphocyte production, survival, and proliferation. During their development, B cells encounter various checkpoints that control cell survival. Under steady state conditions, the number and distribution of B cells is under homeostatic control due to a balance between survival and apoptosis.

Recently, our lab described a new mechanism that regulates B cell survival, which depends on the membranal protein, CD74 (invariant chain, Ii). Our studies have shown that CD74 expressed on B cells is directly involved in shaping the B cell repertoire by regulating mature B cell survival, through a pathway leading to the activation of transcription mediated by the NF-κB p65/RelA homodimer and its co-activator, TAFII105. We demonstrated that CD74 stimulation by its natural ligand macrophage inhibitory factor (MIF) activates the Syk and PI3K/Akt pathways, leading to NF-κB activation, enabling entry of the stimulated B cells into the S phase, an increase in DNA synthesis, cell division, and augmented expression of anti-apoptotic proteins in a CD44-dependent manner.

CLL: Interestingly, both MIF and CD74 have been associated with tumor progression and metastasis. Many studies have demonstrated the overexpression of CD74 in various cancers and its expression has been suggested to serve as a prognostic factor in many of these cancers, with higher relative expression of CD74 behaving as a marker of tumor progression.

Chronic lymphocytic leukemia, the most common leukemia in the Western world, is characterized by the progressive accumulation of small, mature CD5+lymphocytes in the peripheral blood, lymphoid organs and bone marrow (BM). The hallmark of the disease is decreased apoptosis, resulting in accumulation of these malignant cells. We have recently shown that activation of CD74 by MIF on B-CLL cells, initiates a signaling cascade that contributes to tumor progression. This pathway induces NF-κB activation, resulting in the secretion of interleukin 8 (IL-8), which in turn promotes cell survival. In addition, we showed that stimulation of CD74 results in elevated expression of the TAp63 protein, which directly regulates CLL survival. In addition, TAp63 expression elevates the expression of the integrin, VLA-4, particularly during the advanced stage of the disease. VLA-4 expression facilitates migration of CLL cells back to the BM, where they interact with the supportive BM environment that rescues them from apoptosis. These results could form the basis of novel therapeutic.

Colon epithelial cells (CEC): Recent studies including ours suggest that up-regulation of CD74 and MIF on human colon adenomas is in correlation with survival and dysplasia of the CEC. We are currently analyzing changes in gene expression that regulate expression of CD74 or MIF and might result in increased risk of colorectal cancer. These results will show that CD74 is not only a marker of colorectal cancer, but also serve as a therapeutic target.

Schematic representation of the dual role of TAp63 in B-CLL survival affecting cell survival both directly (by elevating Bcl-2 expression) and indirectly (by elevating VLA-4 expression, allowing homing to the BM)