What Are the Genomic Drivers of Childhood T-ALL?

T-cell acute lymphoblastic leukemia (T-ALL) is a type of blood cancer in which too many abnormal T-cells are produced in the bone marrow.

The findings:

A multisite research team identified 15 subtypes of T-cell acute lymphoblastic leukemia (T-ALL), according to a genomic analysis. The subtypes each have distinct genomic drivers, gene expression patterns, developmental states, and clinical outcomes. The research team found that 60% of the genetic changes driving T-ALL cancer cells are in non-coding regions of the genome. DNA in these non-coding regions, which were previously considered "junk," do not build proteins themselves but have important functions that drive the disease.

Why it matters:

The study's findings provide a roadmap for clinicians to classify, risk stratify, and develop targeted therapies to treat children with this aggressive blood cancer. By classifying T-ALL subtypes into four risk levels (very high, high, low, and very low), the study could immediately help clinicians to customize their treatment plans for patients.

T-ALL is an acute leukemia that mainly affects children, in which abnormal T-cells are produced in the bone marrow. About 20% of children and adolescents who are diagnosed with T-ALL experience relapse or do not respond to standard chemotherapy, and long-term survival rates for patients with relapsed or refractory T-ALL is less than 10%.

To identify patients who are at risk for recurrence and intervene with novel therapies, clinicians first need to understand the genetic drivers of their disease. Unlike in B-ALL, another type of acute lymphoblastic leukemia, the genetic underpinnings of T-ALL have never been previously understood.

Who conducted the study:

David Teachey, MD, an attending physician and Director of Clinical Research at the Center for Childhood Cancer Research at CHOP, led the study with Charles Mullighan, MSc, MD, of St. Jude Children's Research Hospital, and colleagues at the Children's Oncology Group, a National Cancer Institute supported clinical trials group. Dr. Teachey is also the co-leader of the Immune Dysregulation Frontier Program.

How they did it:

Dr. Teachey and colleagues performed whole genome and transcriptome sequencing of tumor and remission samples from more than 1,300 children with T-ALL who received the same treatment. The study included a diverse population of patients from the United States, Canada, Australia, Switzerland, and New Zealand.

Quick thoughts:

"This paper completely changes the paradigm of how we think about T-cell acute lymphoblastic leukemia," Dr. Teachey said.

What's next:

"We can now put T-ALL into 15 different baskets of patient subtypes and understand what biologically is causing them, which will help us to develop and repurpose targeted therapies," Dr. Teachey said. "And for the first time, we can appropriately risk stratify patients, which means we can identify the patients at diagnosis who are going to do poorly and those who are going to do well, and then we can start tailoring our therapy based on that diagnosis."

Where the study was published:

"The genomic basis of childhood T-lineage acute lymphoblastic leukemia" appeared in Nature in August.