Research Reveals Genomic Basis for Acute Erythroid Leukemia

Acute erythroid leukemia (AEL) is a high-risk cancer with a poor prognosis, uncertain genetic basis and controversy around diagnosis. This is changing, thanks to the research conducted today by the St. Jude Children's Research Hospital, published in the journal Nature Genetics.

The researchers performed the largest and most comprehensive genomic badysis ever done on AEL and identified six age-related subgroups with mutations and patterns of expression. distinct genes, as well as the results of the treatment.

The badysis revealed that 45% of patients had mutations in signaling pathways that promote uncontrolled cell growth. Investigators have also reported evidence that leukemia may be vulnerable to existing precision drugs.

"Genomic alterations and gene expression profiles were the most important predictors of the outcome of patients with EEL, suggesting that they should be incorporated into the diagnostic criteria and the following: of prognosis, "said corresponding author, Charles Mullighan, MBBS, MD, a member of the St. Jude Department of Pathology.

"These results mark a new era in the understanding and treatment of AEL, an aggressive leukemia that has suffered from diagnostic controversy and poor results," he said.

LEA is a rare subtype of acute myeloid leukemia that is more common in the adult than in the child. AEL often does not respond to conventional treatment and long-term overall survival is less than 10%.

Redefining the AEL

Clbadifying AEL in the spectrum of myeloid leukemia has been a challenge since the description of leukemia almost a century ago. The diagnostic criteria have changed over the decades, and more recently in 2016, but the genome base of AEL has remained uncertain. As a result, in 2016, some cases previously defined as LEAs were reclbadified as AML or Myelodysplastic Syndrome (MDS). AEL, AML and MDS are all myeloid cancers, or cancer of bone marrow cells, but require different treatments of significantly different intensity.

The researchers in this study compared the mutational landscape of 159 children and adults diagnosed with AEL in 1,903 patients with non-AEL-related myeloid disorders, including AML and MDS. . The badysis included sequencing data from the entire genome, whole exome, or whole transcriptome. Patients came from the United States, Europe, Singapore, Japan, and Australia. They went from infants to adults 60 years and older.

Biology

"We found that patients with AEL, AML, and MDS had many of the same mutations, but their frequency and pattern were very different," said first author, Ilaria Iacobucci, Ph.D. .D., Scientist at the Mullighan laboratory. "The results demonstrate that AEL is a specific subtype and offer insights into how the process and outcome of the disease vary in children and adults."

For example, modifications in one or both copies of the TP53 tumor suppressor gene were a feature of a subset of LEP that occurred almost exclusively in older adults. The subset accounted for 32% of the cases in this badysis and was badociated with a poor prognosis. There were no survivors in the long run.

In contrast, about 12% of adult patients belonged to a subgroup defined by mutations in the NPM1 gene and had a good prognosis. More than 87% of the patients were long-term survivors.

It is the genomic alterations that defined the other AEL subgroups:

• NUP98 (rearranged)
• KMT2A (mutated or rearranged)
• DDX41 (mutated)
• Other (without recurrent identifiable fundamental genetic alteration)

Precision medicine

"Identifying the genomic base of AEL has also led to the identification of new therapeutic targets in signaling pathways and early evidence of efficacy," said co-author Torsten Haferlach , MD, of the MLL Leukemia Laboratory Munich. Kinases help regulate gene activity and are frequently mutated in cancer.

For example, a mouse model of AEL that included mutations in TP53 and NTRK1, a kinase in a signaling pathway, was highly sensitive to the inhibitor of larotrectinib. AEL remained undetectable in mice for at least three months after treatment.

"The results highlight the potential role of such inhibitors in future clinical trials," Mullighan said.