Molecular mechanisms behind the survival of resistant/refractory CLL

• Applicant: Dr. Elias Hobeika
• Subject Area: Immunology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 534719412

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder of B cells, representing the most common type of leukemia in Western countries. Expression of the B cell antigen receptor (BCR) is a key feature of most B cell neoplasms including CLL, suggesting that BCR signaling is required for pathogenesis, which is underlined by the clinical success of several BCR signaling inhibitors. However, acquired drug resistance is still a crucial issue that often leads to the relapse of the disease and unfavorable outcome. By generating mouse models allowing for the inducible inactivation of BCR signaling components in CLL cells, we established a tool for the investigation of signal transduction in CLL-like cells. This could contribute to the discovery of potential new targets and therapeutic alternatives for CLL patients. Recently, we addressed the question whether the presence of the BCR is important for CLL development and survival. As a model for CLL, we employed the E gamma-TCL1 transgenic mice, a widely studied mouse line that develops CLL-like disease with age. By inducible inactivation of BCR signaling components in these mice, we identified the surface expression of a functional BCR signaling complex as a uniquely important regulator of CLL-cell survival. However, E gamma-TCL1 mice lacking Igß signaling tail, but not Igα-tail, developed CLL in some cases indicating that Igß-mediated signaling is possibly not as essential for CLL development as signaling emanating from Ig alpha. Inhibitors targeting BCR signaling elements such as the kinases SYK, PI3K or BTK show remarkable clinical effectiveness in clinical trials and CLL therapy. Especially the BTK inhibitor ibrutinib is frequently used in the treatment of CLL. We showed, that deletion of Btk in CLL B cells resulted in an egress of CLL cells from lymphatic organs into the periphery of E gamma-TCL1 mice, an observation similar to CLL patients treated with the BTK inhibitor ibrutinib. Thus, this mouse model possibly can be used to further study the role of lymphocytosis in the treatment of CLL. However, CLL cells developed and survived in the absence of functional BTK expression, questioning the effectiveness of the BTK inhibitor ibrutinib in CLL patients’ treatment. Within this proposal, we aim to study the molecular mechanisms behind the survival of these BTK-deficient resistant CLL clones. Altogether, our findings will contribute to a better understanding of the Igß signaling domain and BTK inhibitor effectiveness in CLL therapy and designate the BCR signaling as potential new therapeutic targets for CLL treatment. We will continue our studies on the role of BCR signaling in CLL and aim at identifying novel targets for therapy.

• DFG Programme: Research Grants