Multiomic signatures identified for rapid detection and treatment of high-risk T-ALL

Researchers from Children's Hospital of Philadelphia (CHOP) have discovered the underlying biology that identifies a subset of patients with acute lymphoblastic leukemia who have a higher risk version of the disease and are more likely to relapse despite treatment. The findings allowed researchers to identify new potential therapeutic treatments for patients with this specific form of cancer with a high risk of recurrence. The findings were published today by the journal Nature Cancer.

Acute lymphoblastic leukemia (ALL) accounts for approximately 30 percent of all pediatric cancers and is the most common cancer in children. While most children with ALL are cured, a significant percentage of patients continue to relapse. ALL affects the immature forms of white blood cells, called lymphocytes and has two types: B-ALL and T-ALL, named for whether B-lymphocytes or T-lymphocytes are affected.

Historically, children with T-ALL fared worse than those with B-ALL. However, with modern therapy, newly diagnosed patients with B-ALL and T-ALL have similar chances of being cured. Nevertheless, while some children with B-ALL respond to therapy after relapsing, most children with T-ALL who relapse are not cured. This is due to a diverse set of causes of T-ALL, not all of which can be treated the same. Therefore, identifying subtypes of T-ALL and potential therapeutic options is critical for patients who relapse and have no other available treatment options.

Building upon encouraging findings published in the journal Nature earlier this year, researchers wanted to better understand cellular and genetic factors contributing to treatment resistance and disease relapse. To do this, researchers relied on single cell sequencing of more than 595,000 immature blood cells or blasts to pinpoint why some of them develop into cases of T-ALL that are at a higher risk of relapsing.

"Generally, cancers like leukemia get stuck along a differentiation path, meaning that the blasts do not go on and form normal blood cells," said co-senior author Kai Tan, PhD, a professor in the Department of Pediatrics and an investigator in the Center for Childhood Cancer Research at CHOP. "By using this technique and comparing cancerous cells to healthy control donor samples, single cell sequencing helped us identify which cells result in these high-risk cancers."

In this study, researchers wanted to link tumor subpopulations with clinical outcome, create an atlas of healthy pediatric blood cell development, and apply single-cell multiomic analysis to a diverse cohort of T-ALL cases.

The researchers identified a subpopulation of bone-marrow progenitor-like (BMP-like) T-ALL associated with treatment failure and overall poor survival. Progenitor cells are descendants of stem cells that can further differentiate into different types of cells. While prior bulk analysis missed specific gene signatures of these very specific cells, the single cell molecular sequencing found a gene signature on these BMP-like cells that predicted poor outcome across multiple subtypes of T-ALL.

By knowing its gene signature, researchers then used in silico and in vitro drug screenings to identify therapies that could potentially target the cells associated with high-risk cancer. The researchers found that venetoclax, an FDA-approved drug used to treat other forms of leukemia and lymphoma, appears to effectively target these BMP-like cells. The researchers hope to design a clinical trial that could test the effectiveness of the drug for patients with the gene signature identified in this study, with the hope that it could help patients with relapsed or refractory disease.

"One of the major challenges in treating T-ALL is that we know certain drugs work for some patients who relapse, but these drugs are not effective for all patients who relapse. Identifying the patients who may benefit from new therapies is critical," said co-senior author David T. Teachey, MD, co-leader of the Immune Dysregulation Frontier Program and an attending physician and researcher at CHOP. "By identifying more gene signatures like what we describe in this study, we will have a much better idea of which therapeutic agents are most likely to help specific subsets of patients, which is the goal of precision medicine."

This study was supported by the Alex's Lemonade Stand Foundation, Gabriella Miller Kids First grant X01HD100702, the Leukemia and Lymphoma Society, Hyundai Hope of Wheels, National Institutes of Health grants R03CA256550, R01CA193776, U10CA180886, R01CA264837, U10CA18099, U24CA114766, U24CA196173, U2CCA233285, U54HL165442, F30-CA-268782, and F30-CA-277965, the St. Baldrick's Foundation, the Pennsylvania Department of Health, the Harrison Willing Memorial Research Fund, the Invisible Prince Foundation, the Aiden Everett Davies Innovation Fund, and the NIH Medical Scientist Training Program grant T32 GM07170. Novartis Inc. funded the original clinical trial in which data used for this study was generated.