Research led by the Wellcome Trust Sanger Institute and the University of Cambridge reveals why some cases of infant B-cell acute lymphoblastic leukemia (B-ALL) remain untreatable, but reveals new targets for future treatments for these children.
ALL mostly affects young children and takes different forms depending on the main cell type driving the cancer. B-ALL is driven by the immune cells known as B lymphocytes or B cells. Childhood ALL was once almost universally fatal, but treatments developed over the last few years mean that survival of children with ALL increased from 10% in the 1960’s to 90% in 2015.
Despite these advances, B-ALL is hard to treat in infants under the age of one year. Treatments effective in other leukemia patients such as bone marrow transplants are ineffective in infant B-ALL. Intensive chemotherapy is the only real option and this treatment still fails in around 50% of cases.
Up to 80% of infant B-ALL cases are linked to rearrangements in the KMT2A gene. Sam Behjati, co-lead investigator of the study and group leader and Wellcome Senior Research Fellow at the Sanger Institute, and colleagues investigated why some cases in this group seem to resist treatment through bulk messenger (m)RNA meta-analysis and a comparison of single lymphoblast transcriptomes with normal developing bone marrow cells.
As described in Nature Medicine, the researchers compared gene expression data from 1,665 childhood B-ALL cases to data from 60,000 normal bone marrow cells from children of a similar age. They found that infant B-ALL had a distinct cellular makeup compared with B-ALL cases in older children. In particular, early lymphocyte precursor cells were common in treatment-resistant infant B-ALL, whereas infant cases that did respond to treatment showed more developed B-cells, in line with B-ALL in older children.
“Cancers with more ‘mature’ early lymphocyte precursors have characteristics that seem to respond better to treatment. These more mature cells are more common in B-ALL in older children but sadly not for our younger patients, meaning the treatment is less effective,” said Jack Bartram, a clinician and senior author of the study from Great Ormond Street Hospital, in a press statement. “The challenge now is to develop our understanding and confirm these suspicions so that we can improve treatments for all patients.”
To try and investigate further the link with lymphocyte precursors, the researchers compared those from infants with resistant B-ALL to non-cancerous versions of these cells. They found that the cancerous cells seemed to have an error in the early differentiation process meaning that they appeared to have a molecular makeup similar to many different cell types. As part of this investigation the researchers found a selection of different markers and pathways that could be targeted in these abnormal cells, which they hope could lead to new treatments being developed in the future.
“Though it is too early to draw definitive conclusions about why B-ALL has much poorer outcomes in infants than in older children, this study offers compelling evidence that the maturity of the cells involved is a key factor,” says Behjati.
“As well as generating new drug targets, these data will allow us to observe how the ‘cell type’ of certain cancers corresponds to patient outcomes, allowing us to better assess disease severity and determine the best course of treatment.”