A Toronto team partly funded by the TFRI has isolated and profiled a group of cells that cause relapse in acute lymphoblastic leukemia (ALL), a type of blood cancer that affects around 400 Canadians every year.
The cells, dubbed diagnosis relapse initiating (dRI) clones, were found to be present in diagnosis samples of blood and bone marrow from patients, meaning that researchers will be able to study relapse prone cells before they progress to overt disease recurrence.
“Being able to isolate these clones at diagnosis, sometimes years prior to disease recurrence, has enabled us to begin to profile the properties that allow these particular cells to survive therapy and act as reservoirs for relapse,” says study first author Stephanie Dobson, a leukemia researcher at the Princess Margaret Cancer Centre (PM).
The team found that dRIs have characteristics that differ from those of the dominant clones present in the diagnosis leukemia samples, helping them survive current chemotherapies and drive recurrence, according to the study published in Cancer Discovery (February 2020).
“We found that these relapse-fated cells were not only genetically unique, but they also possessed drug tolerance, metabolic rewiring and increased properties of stemness contributing to their persistence and seeding of relapse disease,” says Dr. Dobson.
The discovery fills a longstanding gap in our understanding of leukemia relapse. For years, researchers hypothesized that ALL relapse, which occurs in nearly half of all adult patients diagnosed with the disease, happened because certain cells manage to elude chemotherapy due to mutations that arose during chemotherapy exposure. Until now they had not been able to isolate these cells prior to therapy to study how they behaved.
This new study led by PM senior scientist Dr. John Dick fills this gap. It also opens up opportunities to devise drugs that target these resistant cells and prevent relapse from ever occurring.
“This knowledge can be used to enhance our therapeutic approaches for targeting relapse and relapse-fated cells,” says Dr. Dobson.
A complementary paper was published in Blood Cancer Discovery. Together, these papers provide an integrated genomic and functional approach to describing the underlying genetics and mechanisms of relapse for ALL.
Relapse fated latent diagnosis subclones in acute B lineage leukaemia are drug tolerant and possess distinct metabolic programs
Stephanie M. Dobson, Laura García-Prat, Robert J. Vanner, Jeffrey Wintersinger, Esmé Waanders, Zhaohui Gu, Jessica McLeod, Olga I. Gan, Ildiko Grandal, Debbie Payne-Turner, Michael N. Edmonson, Xiaotu Ma, Yiping Fan, Veronique Voisin, Michelle Chan-Seng-Yue, Stephanie Z. Xie, Mohsen Hosseini, Sagi Abelson, Pankaj Gupta, Michael Rusch, Ying Shao, Scott R. Olsen, Geoffrey Neale, Steven M. Chan, Gary Bader, John Easton, Cynthia J. Guidos, Jayne S. Danska, Jinghui Zhang, Mark Minden, Quaid Morris, Charles G. Mullighan and John E. Dick
This study was partially funded by a Terry Fox New Frontier Program Project Grant in Development of Stemness-Based Prognostic Biomarkers and Therapeutic Targets