CHMP5 Dependency as a Posttranslational Vulnerability in T-Cell Leukemia
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer that initiates in the precursor cells that generate the T-cells required for immunity. The disease is common in children, adolescents and young adults, a population that includes many active and future military service members and their families. Although much progress has been made in our understanding of this disease and initial chemotherapy treatment can improve patient conditions, T-ALL remains a major clinical problem. In particular, many T-ALL patients often relapse with a more aggressive disease and by current estimates, less than 25% of these relapse patients achieve a five-year survival mark. Moreover, survivors of T-ALL (and many childhood cancer survivors) often have to live with long-term debilitating effects of current treatment regimens including mental disabilities, organ dysfunction and secondary cancers. This is even more pertinent for military service members who, due to the nature of their service, are exposed to leukemia-associated environmental risk factors like ionizing radiations and chemical carcinogens. Thus, there is a major need to discover alternative strategies that will provide more potent and less toxic activity against leukemia cells. In this application, we propose to investigate how a small adaptor protein CHMP5 (Charged Multivesicular Body Protein-5), serendipitously identified by our group as a key player in T-cells, functions as a critical orchestrator of the stability of cellular proteins essential for leukemia development. So far, many anti-cancer strategies are focused on targeting the genes and transcriptional pathways driving individual cancers but these drugs often end up selecting for new cancer mutations that promote cancer re-emergence. We think that CHMP5 protein is stabilized as a consequence of T-ALL oncogene activities after which it in turn crucially orchestrates the stability of leukemiapromoting proteins and pathways. As such, targeting CHMP5 represents a novel alternative strategy that directly targets and causes the degradation of cancer-inducing proteins and/or their intermediaries. Because cellular hubs that control protein stability often integrate many vital pathways including oncogenic pathways, we think this approach may have broad activity against genetically distinct T-ALL subtypes. We specifically propose here to define how CHMP5 contributes to the process of leukemia development and to identify specific candidate proteins that promote CHMP5 expression and activity in T-ALL cells. We envisage that interfering with CHMP5 protein expression or activity can be a potent strategy to durably eliminate T-ALL cells. Results from our investigations will not only generate robust preliminary data that will position us to secure additional funding for our future research they will also be the first steps to achieving a better proteomic understanding of T-ALL disease pathogenesis and have the potential to uncover specific ways to deplete CHMP5 for therapeutic benefits. Novel and more potent drugs (including those aimed at CHMP5 depletion as we propose here) will benefit the many T-ALL patients that include children, adolescents and young adults who comprise a prime population of active military service members, potential recruits and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910306
Entities
People
- Stanley Adoro
Organizations
- Case Western Reserve University
- United States Army