AU Maya Jaffe

Research – JNCI – The ‘omics of Obesity in B-cell Acute Lymphoblastic Leukemia

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jncmon_2023_61coverThe ‘omics of Obesity in B-cell Acute Lymphoblastic Leukemia
Geitgey DK, Lee M, Cottrill KA, Jaffe M, Pilcher W, Bhasin S, Randall J, Ross AJ, Salemi M, Castillo-Castrejon M, Kilgore MB, Brown AC, Boss JM, Johnston R, Fitzpatrick AM, Kemp ML, English R, Weaver E, Bagchi P, Walsh R, Scharer CD, Bhasin M, Chandler JD, Haynes KA, Wellberg EA, Henry CJ. (2023) J Natl Cancer Inst Monogr.
PMID: 37139973

Previous studies suggest that cancer patients with obesity fare worse than patients without obesity, and that cancerous B-cells get help from adipocytes (fat cells) to protect themselves from chemotherapy drugs that are used to kill cancer cells. Adipocytes could stimulate the cancerous B-cells to change their gene expression, protein make-up, metabolism, or drug uptake mechanisms, but so far studies have not determined which if any occur in B-cell acute lymphoblastic leukemia (B-ALL). In this multi-lab study led by Curtis Henry’s lab at Emory, we measured gene expression (RNA transcription), proteins, and metabolites in B-ALL cells with and without exposure to chemical signals from adipocyte cells. Our data from cultured cells show that adipocyte-stimulated B-ALL cells shift gene expression and protein levels that regulate metabolism, oxidative stress protection, cell survival, B-cell development, and chemoresistance. Data from a mouse model show that a high-fat diet reduces normal immune activity of healthy B-cells. These results provide a clearer understanding of the molecular differences of B-ALL cancer cells in patients with obesity, and could inform drug development to improve treatment outcomes.

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Research – GEN Biotech – Synthetic Reader-Actuators Targeted to Polycomb-Silenced Genes Block Triple-Negative Breast Cancer Proliferation and Invasion

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SRA_TNBC_2023_thumbSynthetic Reader-Actuators Targeted to Polycomb-Silenced Genes Block Triple-Negative Breast Cancer Proliferation and Invasion
Hong L, Williams NL, Jaffe M, Shields CE, Haynes KA. (2023) GEN Biotechnology. https://www.liebertpub.com/doi/10.1089/genbio.2023.0020

An exciting new approach for cancer therapy is to turn on genes within the cancer cells that can stop them from growing and spreading. This approach, called epigenetic therapy, uses small molecules (inhibitors) to block chromatin-modifying proteins that play a role in silencing anti-cancer genes. However, this approach has shown disappointing results in clinical trials for solid cancers, perhaps due to biological limitations. For example, inhibitors can accidentally activate the proteins they are supposed to block (e.g. EZH inhibitors promote EZH2/FOXM1 complexes, Mahara et al 2016), and inhibitors can’t turn on important gene-regulating proteins that are damaged in many cancers. To overcome these limitations we have developed a new tool, synthetic reader-actuators (SRAs), that directly targets chromatin-silenced regions, activates the pre-initiation complex (PIC), and turns on gene transcription. In this report we tested SRAs in triple negative breast cancer cells (BT-549) and identified 122 activated genes. SRA-expressing BT-549 cells showed reduced spheroid size over time, loss of invasion, and activation of apoptosis. While epigenetic drugs have not been successful in many clinical trials, by using synthetic proteins we showed that robust epigenetic reprogramming is possible in cells from solid cancers.

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