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.
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.
Chua BA, Lennan CJ, Sunshine MJ, Dreifke D, Chawla A, Bennett EJ, Signer RAJ. Hematopoietic stem cells preferentially traffic misfolded proteins to aggresomes and depend on aggrephagy to maintain protein homeostasis. Cell Stem Cell. 2023.