Researchers reveal a potential therapeutic strategy against T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of leukemia in which too many T-cell lymphoblasts, or immature white blood cells, are found in the bone marrow and blood. Researchers from Rutgers Cancer Institute of New Jersey, the state's only National Cancer Institute-designated Comprehensive Cancer Center, recently discovered that a mitochondrial uncoupling drug is toxic against leukemic cells, revealing a potential therapeutic strategy against T-ALL. Daniel Herranz, PharmD, PhD, resident researcher at Rutgers Cancer Institute and assistant professor of pharmacology at Rutgers Robert Wood Johnson Medical School, is senior author of the work and shares more about the findings published in the April 19 online edition of Blood [doi.org/10.1182/blood.2020008955].

Why is this topic important to explore for this particular patient population?

T-ALL is a hematological malignancy that predominantly affects children, but can also occur in adults. Even if recent advances in treatments with intensified chemotherapy regimens result in most patients being cured, 20 to 50 percent of patients show primary resistance to treatments or eventually relapse. Regretfully, the prognosis is dismal in these cases, and patients ultimately die of their disease. Thus, there's a clear need to identify novel therapeutic targets in T-ALL that might help improve cure rates.

Describe the work and what you and your colleagues found.

We describe a novel mitochondrial uncoupling drug with good chemical properties for its use in living organisms (in vivo). This drug affects the functionality of mitochondria, which is the powerhouse of the cell. We decided to test its effects in T-ALL since prior results from the lab suggested that mitochondrial activity could be of critical importance for leukemia cells. Our results demonstrate that mitochondrial uncoupling shows a strong anti-leukemic effect not only in T-ALL cell lines outside of living organisms, but also in mouse models of leukemia in vivo, and in mice harboring patient-derived T-ALL xenografts.

What are the implications of these findings and what are future steps pertaining to this work?

We provide in vivo evidence of the therapeutic potential of mitochondrial uncoupling drugs in T-ALL. Thus, our results offer a new therapeutic strategy for the treatment of leukemia, which might be particularly relevant for relapsed cases with few therapeutic alternatives. Additional studies already undergoing in the lab should elucidate whether mitochondrial uncoupling might synergize with other drugs currently used in the treatment of T-ALL or whether treatment with this drug uncovers novel vulnerabilities in leukemic cells. Even more important, clinical trials in T-ALL patients in the short/mid-term should demonstrate the efficacy of mitochondrial uncoupling in this disease.