Targeting Leukemia Stem Cells by Disrupting Translational Fidelity


IN PARTNERSHIP WITH LEUKEMIA & LYMPHOMA SOCIETY AND THE PAUL G. ALLEN FRONTIERS GROUP (2020-PRESENT)

Robert Signer, PhD, University of California San Diego

Two barriers in the treatment of acute myeloid leukemia (AML) include its low mutational burden, which limits neoantigen presentation, and the presence of treatment-resistant leukemia stem cells (LSCs), which can cause relapse. Any successful long-term treatment of AML will have to target LSCs to prevent recurrence. Robert Signer and his colleagues are tackling these issues by targeting the fidelity of protein translation in the LSCs. Although every cell type must have tight control over translation of mRNA into proteins, Dr. Signer’s team has found that LSCs are exquisitely sensitive to perturbations in translation, and this may represent a mechanism for their eradication.

To examine this potential therapeutic approach further, they are using genetic mouse models of translational stress to delve into the mechanism of how errors in translation decrease the fitness of LSCs. They will also use novel aminoglycoside compounds to pharmacologically perturb translational homeostasis in AML and measure if this is a viable strategy for treatment. Finally, they will study whether the increase in translational errors upregulates neoantigen presentation on the LSCs to make them more visible to the immune system. In this way, they plan to target translational fidelity with a two-pronged technique of decreasing the overall fitness of the stem cells while simultaneously increasing neoantigen presentation by inducing translational errors.

PUBLISHED RESEARCH

Magee JA, Signer RAJ. Developmental Stage-Specific Changes in Protein Synthesis Differentially Sensitize Hematopoietic Stem Cells and Erythroid Progenitors to Impaired Ribosome Biogenesis. Stem Cell Reports. 2021.

Kruta M, Sunshine MJ, Chua BA, Fu Y, Chawla A, Dillingham CH, Hidalgo San Jose L, De Jong B, Zhou FJ, Signer RAJ. Hsf1 promotes hematopoietic stem cell fitness and proteostasis in response to ex vivo culture stress and aging. Cell Stem Cell. 2021.

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