Crucial Mutations Found in T-Cell ALL

Researchers at The Institute of Cancer Research, London, have discovered seminal genetic events that may be responsible for T-cell acute lymphoblastic leukemia (T-ALL) in children and young adults. Caroline Furness, MA, MBBChir, MRCPCH of the Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK, and colleagues report in Leukemia that identifying founder genetic mutations may pave the way for new targeted therapies in this patient population.

Because T-ALL is biologically diverse, the investigators decided to study a single, common subtype of T-ALL: patients with STIL-TAL1 fusion. They conducted a diagnostic DNA evaluation of 19 patients between the ages of 1 and 24 years, and found that the gene fusion STIL-TAL1, along with inactivation of the CDKN2A gene, appeared to be early or truncal events. Other recurrent genetic changes, including mutations of NOTCH1 and PTEN, appeared to be secondary and subclonal.

The team theorizes that it may be possible to treat T-ALL by targeting the signaling pathways that are affected by the gene fusion STIL-TAL1. They hope these new findings may lead to more effective and less toxic treatments.  It is possible that these findings may be used to undercover therapies that benefit children who relapse.

The researchers note that, based on current data, it is difficult to know whether STIL-TAL1 fusion or CDKN2A loss is an initiating event. The study showed that malignant cells from a significant number of patients had errors in PTEN. Because these errors appeared to occur later than the STIL-TAL1 gene fusion, it is possible that PTEN gene alterations help to maintain leukemia growth and survival. If that is the case, this information could lead to yet another targetable treatment approach.

The team used single-cell genetics to examine clonal complexity and the sequence of mutational events in STIL-TAL1–positive T-ALL. Using single-cell multicolor FISH, the researchers found the earliest detectable leukemia subclone contained the STIL-TAL1 fusion and copy number loss of 9p21.3 (CDKN2A/CDKN2B locus). In three of the cases, the team was able to conduct a multiplex qPCR and a phylogenetic analysis. This produced branching evolutionary trees and provided a snapshot history of T-ALL evolution in this leukemia subtype. The study confirmed that mutations in key T-ALL drivers, including NOTCH1 and PTEN, were subclonal. These drivers also were reiterative in distinct subclones.

Furness and colleagues conducted xenograft studies to further examine the subclonal origin and genetic diversity of propagating or self-renewing cells in STIL-TAL1–positive ALL. They found that multiple subclones “read out” in the mice, suggesting the existence of genetically diverse stem cells. Furness and colleagues wrote that further studies are warranted, with the goal of identifying exactly which subclones may harbor the proliferative potential to fuel disease progression, relapse, and drug resistance.