UC San Diego

Acute myeloid leukemia (AML) is the most common and deadly leukemia in adults. Although most AML patients respond to first-line chemotherapy, relapse is common. Thus, the five-year overall survive rate remains under 50%. The high relapse rate of patients who achieve “complete remission” is largely due to the difficulties of eradicating minimal residual AML cells, using current therapeutic strategies. Thus, additional therapies to target and eradicate residual AML are greatly needed.

In the Chapter 1, we report the development of a novel nanoparticle-based AML vaccination immunotherapy for the treatment of AML. Our vaccine platform utilizes AML cell membrane-coated nanoparticles (AMCNPs), in which immune stimulatory adjuvant-loaded nanoparticles are coated with leukemic cell membrane material. The AMCNP vaccine stimulates leukemia-specific immune responses by co-delivering membrane-associated antigens along with adjuvants to antigen-presenting cells. The AMCNP vaccines were efficiently acquired by antigen-presenting cells in vitro and in vivo and stimulate antigen cross-presentation. Vaccination with AMCNPs significantly enhanced antigen-specific T cell expansion and effector function. Furthermore, in an AML post-remission vaccination model, AMCNP vaccination significantly enhanced survival in comparison to control vaccination. Our AMCNP vaccination strategy is multi-antigenic, fully personalized, and obviates the need for neoantigen identification. Thus, AMCNPs are a promising platform that can be further developed as an AML vaccination immunotherapy.

In chapter 2, we examined the post-transcriptional regulation of the AML1-ETO oncofusion gene. The AML1-ETO oncofusion gene is created by the t(8;21)(q22;q22) chromosomal translocation, which characterizes a common AML subtype [t(8;21) AML]. Post-transcriptional regulation of gene expression is often mediated through interactions between trans-factors and cis-elements within transcript 3'-untranslated regions (UTR). AML1-ETO uses the 3’UTR of the ETO gene, which is not normally expressed in hematopoietic cells. Therefore, the mechanisms regulating AML1-ETO expression via the 3’UTR are attractive therapeutic targets. Here, we identify a negative regulatory element within the AML1-ETO 3’UTR and demonstrate that the let-7b microRNA directly represses AML1-ETO through this site, inhibits the proliferation of t(8;21) AML cell lines, rescues expression of AML1-ETO target genes, and promotes differentiation. We conclude that AML1-ETO is posttranscriptional regulated by let-7b, which contributes to the leukemic phenotype of t(8;21) AML.