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Integrated Genomic Analysis Highlights Potential Strategy for Overcoming Some ALL Resistance

NEW YORK – Based on findings from an integrated genomic, transcriptomic, and epigenomic analysis of acute lymphoblastic leukemia (ALL) cases, a St. Jude Children's Research Hospital-led team has proposed a potential treatment alternative treatment for glucocorticoid steroid-resistant ALL patients.

"The findings point to the potential benefit of combining venetoclax with current remission-induction therapy as a strategy to overcome steroid resistance and improve the effectiveness of ALL chemotherapy," co-senior and corresponding author William Evans, a precision medicine, pharmaceutical sciences, and integrated biomedical sciences researcher affiliated with St. Jude and the University of Tennessee, said in a statement.

As they reported in Nature Cancer on Monday, Evans and his colleagues did array-based gene expression, microRNA expression, SNP, and/or methylation profiling on samples from 225 recently-diagnosed pediatric B-lineage ALL cases, combining these data with exome sequences for 201 of the pediatric ALL cases to search for somatic variants, small insertions and deletions, copy number changes, regulatory shifts, and other changes associated with resistance to glucocorticoid steroids such as prednisolone or dexamethasone.

"Drug resistance is a major cause of treatment failure for children and adults with disseminated cancers like leukemia," Evans explained, noting that roughly 20 percent of pediatric ALL cases and even more ALL cases in adults are marked by resistance to such steroid treatment.

Together, the data highlighted hundreds of genomic features with apparent ties to glucocorticoid resistance, the researchers reported, noting that these alterations centered on dozens of known resistance genes and 14 new genes.

The candidate resistance gene set, validated with data from nearly 500 more pediatric and adult ALL cases, included a gene called CELSR2 that the team assessed in more detail with single-cell RNA sequencing experiments, CRISPR-Cas9-based gene editing, gene expression network analyses, ATAC-seq, and mouse xenograft model experiments.

Among other things, the investigators found that alterations leading to lower-than-usual levels of CELSR2 were linked to lower glucocorticoid treatment response and enhanced levels of a protein called BCL2, which can be targeted by the drug venetoclax. On the other hand, mouse xenograft models missing CELSR2 appeared more susceptible to prednisolone treatment when venetoclax treatment was used in tandem.

"Low CELSR2 expression was documented in approximately half of glucocorticoid-resistant ALL patients (45 percent)," the authors wrote, "suggesting that co-treatment with venetoclax could impact a large number of patients, and this combination may have even broader utility because other mechanisms of glucocorticoid resistance involved lower [glucocorticoid receptor] expression or function."

These and other results from the study "illustrate the power of an integrative genomic strategy for elucidating genes and pathways conferring drug resistance in cancer cells," the authors suggested.

More generally, they noted, the approaches used in the ALL drug resistance study "represent a broad strategy for discovering genetic and epigenetic mechanisms by which cancer cells develop resistance to chemotherapy, and for revealing therapeutic strategies to mitigate resistance."

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