Refining Leukemia Classification for More Accurate Diagnoses


Some of the new subtypes are similar to previously identified ones but show similar prognoses to established subtypes.

By identifying new subtypes of B-cell acute lymphoblastic leukemia (B-ALL), investigators believe they can improve their diagnoses and treatments, according to a new report. B-ALL is the most common pediatric malignancy with its several known subtypes and is the leading cause of pediatric cancer death.

Investigators from St. Jude’s Children’s Research Hospital in Memphis utilized integrated genome analytics and RNA sequencing in 1988 pediatric and adult cases of ALL in order to understand a revised set of subtypes. The team chose to focus on the B lymphoid transcription-factor gene PAX5, in which 2 subtypes of B-ALL often show alterations on. The analysis included patients from St. Jude’s, the Children’s Oncology Group, and adult cancer cooperative studies.

The investigators classified 23 B-ALL subtypes including eight new subtypes to find their unique genomic clinical features and outcomes. Studying PAX5 uncovered two new subtypes which now account for nearly 10% of previously uncategorized cases of B-ALL.

“The most striking finding was the sheer diversity of the types of genetic change that define groups of ALL; the multiple new groups that were unrecognized, and the marked differences in frequency of each subgroup according to age,” study author Charles Mullighan, MBBS (Hons), MSc, MD, told Rare Disease Report®. “Many of the groups are strongly associated with the risk of relapse in both children and adults, so it is key to use accurate genetic testing of the leukemic cells at diagnosis to guide treatment.”

These 2 new subtypes are a high-risk type of B-ALL that often occurs in adults, occurring when transcription factors BCL2 and MYC or BLC6 get rearranged. Mullighan called this subtype a “dismal diagnosis” in a press release.

However, recognizing the subtype early enough could lead to alternative therapies for patients, Mullighan added.

The team believes their robust classification system for B-ALL can be integrated into the clinical diagnosis of acute lymphoblastic leukemia (ALL). Part of the goal is to speed the development of individual treatment plans that are customized for these patients. Further down the line, the investigators believe this will lead to the development of new targeted therapies to more effectively treat leukemia.

“In addition, we showed that the subgroup-defining genetic alterations can be mutations, deletions, or chromosomal rearrangements, so accurate diagnostics need genomic sequencing. The paper showed that RNA (Transcriptome) sequencing, which is available in many centers, can be effectively used to do this,” Mullighan said.

The investigators also explained their identification of the new subtypes:

  • NUTM1 gene rearrangement can contribute to treatment vulnerability
  • HLF gene rearrangement to multiple genes, both TCF4 and TCF 3
  • Three subtypes that don’t have names yet, but are related to ETV6-RUNX1, KMT2A, and ZNF384. They have risks and prognoses similar to what they will eventually be named for.
  • There were subtypes that formed from mutations, including the IKZF1 gene (a high-risk marker for B-ALL) that mutated to become IKZF1 N159Y.

The press release added that patient samples from many of the B-ALL subtypes are available from St. Jude’s data portal to the international scientific community for further research, with no obligation to collaborate.

The study, titled “PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia,” was published in Nature Genetics.

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