23 March 2020

Scientists have found a new link between a gene and glucocorticoid resistance in patients with acute lymphoblastic leukaemia (ALL), it has been announced.

Researchers at St. Jude Children’s Research Hospital, Tennessee, USA, identified the gene, CELSR2, through the analysis of multiple dimensions of the genome, including whole genome sequencing, gene expression, and epigenetics. The researchers believe their discovery is a proof that their integrative genomics approach can provide new insights into drug resistance in blood cancers.

CELSR2 is one of 14 newly identified genes implicated in resistance to glucocorticoids. These drugs are crucial to the successful ALL treatment.

The team’s findings appeared in Nature Cancer. Dr William Evans, who led the research, said: “Drug resistance is a major cause of treatment failure for children and adults with disseminated cancers like leukaemia.

“Steroids play an essential role in the treatment of acute lymphoblastic leukaemia. About 20% of children with acute lymphoblastic leukaemia and twice as many adults are highly resistant. Yet, the underlying cause of resistance often remains unknown.”

The team’s work showed that decreased levels of CELSR2 in leukaemia cells were strongly associated with increased glucocorticoid resistance in lab tests. Reduced expression of CELSR2 was found in about half of child and adult patients.

The mechanism behind this effect is thought to be increased expression of the protein BCL2 which inhibits a cell death pathway. BCL2 itself can be inhibited by the drug venetoclax, and in lab experiments the researchers discovered a synergistic effect of combining venetoclax with glucocorticoids in leukaemia cells with low CELSR2 expression.

Dr Evans said: “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 chemotherapy.”

Source: Autry RJ, Paugh SW, Carter R, Shi L, Liu J, Ferguson DC, Lau CE, Bonten EJ, Yang W, McCorkle JR, Beard JA, Panetta JC, Diedrich JD, Crews KR, Pei D, Coke CJ, Natarajan S, Khatamian A, Karol SE, Lopez-Lopez E, Diouf B, Smith C, Gocho Y, Hagiwara K, Roberts KG, Pounds S, Kornblau SM, Stock W, Paietta EM, Litzow MR, Inaba H, Mullighan CG, Jeha S, Pui C-H, Cheng C, Savic D, Yu J, Gawad C, Relling MV, Yang JJ, Evans WE (2020) “Integrative genomic analyses reveal mechanisms of glucocorticoid resistance in acute lymphoblastic leukemia”, Nature Cancer, doi: 10.1038/s43018-020-0037-3


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