Study: Newly Characterized Mutation May Define Novel Pediatric AML Subtype


The investigators identified this in 9% of relapsed cases of pediatric acute myeloid leukemia, but it also was present in primary samples.

A new mutation was identified in 9% of relapsed cases of pediatric acute myeloid leukemia (AML) that may define a new subtype of the disease, according to the results of a new study, published in Blood Cancer Discovery, a journal of the American Association for Cancer Research.

Although investigators identified the mutation in samples of relapsed AML, they found that, in many cases, the mutation was also present in primary samples, and it was mutually exclusive with other subtype-defining AML mutations.

The mutation is a tandem duplication, which is a series of adjacent repeats of a DNA sequence, of exon 13 of the gene UBTF, which normally promotes expression of the cell’s protein translation machinery.

AML is a relatively rare form of blood cancer that affects both adults and children. Although investigators have identified several AML driver mutations that physicians use to stratify patients’ risk and help guide treatment decisions, much of this research has been performed on primary cancers. Klco and colleagues wanted to instead investigate relapsed AML to identify mutations that may drive recurrence.

The investigators performed RNA, target capture, whole-exome, and whole-genome sequencing on a cohort of 136 samples of relapsed AML.

They validated their results using an expansion cohort of transcriptional data from an additional 417 cases.

Additionally, they identified known drivers of AML, such as fusion involving KMT2A and NUP98, as well as several rate mutations in relapsed cases.

However, they were interested in the UBTF tandem duplication, because they had only rarely been observed in myeloid cancers and because they were found in 9% of individuals, which is a relatively high proportion.

In the expansion cohort, investigators found that UBTF tandem duplications were not found alongside mutations that define common or rare AML subtypes. However, they do frequently coincide with mutations in FLT3 and WT1, 2 commonly mutated genes in AML that are sometimes found in the absence of subtype-defining drivers.

These genes are not though to drive oncogenic transformation themselves.

UBTF tandem duplications were found in all samples with WT1 and FLT3 mutations that had no driver mutation identified.

The results suggest that UBTF tandem duplications may be the driver event in such cases, but the duplication must be present at the onset of cancer development and should be observed in primary cancers.

Investigators identified 4 individuals in the expansion cohort with matched primary and recurrent samples, with the recurrent samples having a UBTF tandem duplication.

In all 4 cases, the UBTF tandem duplication was present in the primary sample.

Additionally, the investigators think that the UBTF tandem duplication can be useful for risk stratification.

They used data from the COG AAML 1031 trial and found that individuals with UBTF tandem duplications had a 20% lower 5-year survival, a 15% lower 5-year event-free survival, and a higher likelihood of minimal residual disease positivity following therapy.

These characteristics were independent of co-occurring FLT3 and WT1 mutations.

“We suspected that we were missing something in the pediatric AMLs where we could only find a FLT3 or WT1 mutation. We think UBTF tandem duplications are that thing,” Jeffery Klco, MD, PhD, director of the division of hematopathology and molecular pathology at St. Jude Children’s Research Hospital, said in a statement. “As we work toward proving that UBTF tandem duplications are really a driver of AML, that will open up opportunities for identifying targeted therapies that could work for this subtype of AML.”

Limitations of the study include the lack of integrated computation framework capable of automatically identifying UBTF tandem duplications, potentially resulting in an underestimation of the percentage of UBTF­-mutated samples.

Additionally, there was a relatively small number of pediatric AML samples available for sequencing.


Newly characterized mutation may define novel pediatric AML subtype. American Association for Cancer. February 17, 2022. Accessed February 14, 2022. Email.

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