25 February 2022

A mutation identified in some relapsed cases of paediatric acute myeloid leukaemia (AML) could define a new subtype of the disease, US researchers have reported.

The mutation, tandem repeats of exon 13 in the UBTF gene, is linked to an increased risk of relapse. This, they add, should mean the leukaemia should be treated more aggressively.

The research was jointly led by Dr Jeffrey Klco from St. Jude Children’s Research Hospital in Memphis, Xiaotu Ma, also from St Jude, and Soheil Meshinchi from Fred Hutchinson Cancer Research Center in Seattle.

The team performed whole-genome sequencing, whole-exome sequencing, target capture sequencing and RNA sequencing on 136 samples of relapsed AML. They went on to validate their results using an expansion cohort of transcriptional data from an additional 417 cases.

Writing in the journal Blood Cancer Discovery, the team say they identified known drivers of AML, such as fusions involving KMT2A and NUP98, as well as several rare mutations enriched in relapsed cases.

They were particularly interested in a mutation in the UBTF gene, tandem duplications of exon 13, which was found in 9% of patients.

The mutations in many classical cancer driver genes are hotspot mutations. But Ma said that because the duplication they observed is in almost the same spot in UBTF with such a high recurrence, they believed this mutation had to be functional.

When they examined the expansion cohort, UBTF tandem duplications were not found alongside mutations that define common or rare AML subtypes.

They were found to coincide frequently with mutations in FLT3 and WT1. These are two commonly mutated genes in AML that are sometimes found in the absence of subtype-defining drivers, but which are not believed to drive oncogenic transformation.

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

The team say their findings suggest UBTF tandem duplications could be the driver event. However, if that were the case, the duplications must be present at the onset of cancer development and should therefore be observed in primary cancers.

To investigate further, the researchers identified four patients in the expansion cohort with matched primary and recurrent samples, and whose recurrent samples had a UBTF duplication. In all four cases, the UBTF tandem duplication was present in the primary sample.

Ma said: “Proving it’s a functional driver will definitely take some time, but we really think that will be the case.”

They believe UBTF tandem duplications could be used for risk stratification, which they investigated using data from the COG AAML1031 trial. They found that patients with UBTF tandem duplications had a 20% lower five-year overall survival, a 15% lower five-year event-free survival, and a higher likelihood of minimal residual disease after therapy.

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

Dr Klco said: “Once kids with AML experience a relapse, their likelihood of long-term survival really plummets. Recognising at diagnosis that a child has an AML with the UBTF tandem duplication could indicate that they’re at a high risk of relapse, and their leukaemia should be treated more aggressively.

“We suspected that we were missing something in the paediatric AMLs where we could only find a FLT3 or WT1 mutation. We think UBTF tandem duplications are that thing.

“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.”

Source: Umeda M, Ma J, Huang BJ, Hagiwara K, Westover T, Abdelhamed S, Barajas JM, Thomas ME, Walsh MP, Song G, Tian L, Liu Y, Chen X, Kolekar P, Tran Q, Foy SG, Maciaszek JL, Kleist AB, Leonti AR, Ju B, Easton J, Wu H, Valentine V, Valentine MB, Liu YC, Ries RE, Smith JL, Parganas E, Iacobucci I, Hiltenbrand R, Miller J, Myers JR, Rampersaud E, Rahbarinia D, Rusch M, Wu G, Inaba H, Wang YC, Alonzo TA, Downing JR, Mullighan CG, Pounds S, Babu MM, Zhang J, Rubnitz JE, Meshinchi S, Ma X, Klco JM. (2022) “Integrated genomic analysis identifies UBTF tandem duplications as a recurrent lesion in pediatric acute myeloid leukaemia.” Blood Cancer Discovery, doi: 10.1158/2643-3230.BCD-21-0160.

Link: https://aacrjournals.org/bloodcancerdiscov/article/doi/10.1158/2643-3230.BCD-21-0160/681551/Integrated-genomic-analysis-identifies-UBTF-tandem

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