Researchers uncover new subtype of pediatric AML defined by UBTF tandem duplications

By CH News On Dec 14, 2021

Dec 14, 2021

2 minutes reading

Source/Disclosures Published by:

Source:

Umeda M, et al. Summary LBA-4. Presented at: ASH Annual Meeting and Exposition. Dec 11-14, 2021; Atlanta.

disclosures:
Umeda does not report any relevant financial disclosures. See summary for all relevant financial disclosures from other researchers.

ADD TOPIC TO EMAIL ALERTS

Receive an email when new articles are posted

Enter your e-mail address to receive an e-mail when there are new articles on . ” data-action = “subscribe” > Subscribe

We were unable to process your request. Try again later. If this problem persists, please contact customerservice@slackinc.com.

Back to Healio

Upstream binding transcription factor tandem duplications, or UBTF-TDs, identified by integrated genomic analysis, represent a new subtype of acute myeloid leukemia that previously had no known oncogenic driver, study results showed.

Researchers also identified associations of UBTF-TDs with FLT3-ITD and WT1 mutations, as well as adolescent age and poor outcomes.

The findings, presented at the ASH Annual Meeting and Exposition, shed light on recognized changes that will be crucial for future risk stratification of pediatric AML, the researchers said.

“AMLs with UBTF tandem duplications have so far been considered no-driver cases or FLT3+ leukemia,” Masayuki Umeda, mD, postdoctoral researcher in the lab of Jeffisy M. Klco, doctor, doctorate, in the pathology department at St. Jude Children’s Research Hospital, Healio said. “Identification of the driver change can lead to accurate risk stratification depending on gene change or molecular targeting therapy based on the molecular mechanism behind leukemogenesis.”

Relapse is common in children with AML, resulting in a poor prognosis and a 5-year survival rate of 68%. However, according to researchers, studies have not fully characterized the molecular basis leading to relapse in pediatric AML.

Umeda and colleagues used RNA sequencing, whole-genome sequencing, and target-capture sequencing to perform integrated profiling of 136 relapsed pediatric AML cases, to understand the genetic landscape of pediatric AML at relapse.

They identified not only well-characterized fusion oncoproteins, including those involving KMT2A (n = 36, 26.5%) or NUP98 (n = 18, 13.2%), but also somatic mutations in UBTF in 12 cases (8 .9%). Only 10 UBTF mutations had been previously reported and all within the cohort were heterozygous in-frame exon 13 tandem duplications.

To better detect UBTF-TD, the researchers applied a soft-clipped read-based screening method to RNA sequencing data from 417 additional pediatric AMLs. This led to the identification of 15 additional UBTF TDs, many of which were never reported.

UBTF-TD AMLs were common in early adolescence (median age, 12.6 years; range, 2.4-19.6), and approximately two-thirds of cases had normal karyotype (n = 12) or trisomy (n = 7). Researchers often observed FLT3-ITD (44.4%) and WT1 mutations (40.7%) with UBTF-TDs, which exclude each other from NUP98 and KMT2A rearrangements and other recurrent fusion oncoproteins.

Data from four cases at multiple AML time points suggested that UBTF-TD is a clonal alteration, and analysis of transcriptome data showed that UBTF-TD AMLs had an expression pattern similar to that of NPM1 mutant and NUP98-NSD1 AML subtypes, including NKX2-3 and HOXB cluster genes. This indicated, according to researchers, that UBTF-TD is a unique pediatric AML subtype.

High variant allele frequency at relapse and diagnosis showed that UBTF-TD is a clonal event in leukemogenesis.

Closer examination of UBTF-TDs in cord blood CD34+ cells showed that overexpression promotes colony-forming activity and cell growth, resulting in cells with persistent blast-like morphology and expression patterns similar to those of UBTF-TD AML in patients, Umeda said.

The researchers then looked at prevalence in larger de novo cohorts and identified UBTF-TDs in 4.3% of patients in the all-pediatric AAML1031 cohort (n = 45 of 1,035), with a lower prevalence in the BeatAML and TCGA cohorts. UBTF-TDs in the AAML1031 cohort continued to be mutually exclusive with known AML molecular subtypes of AML and were common with FLT3-ITD (66.7%) and WT1 (40%) mutations and normal karyotype or trisomy 8.

Analysis of clinical outcomes showed associations of UBTF-TD AMLs with shorter OS (median, 2.3 years) and high rates of minimal residual disease (76% after first induction therapy).

“We need to collect more clinical data from AML with UBTF tandem duplication to decide how to treat this subtype, including [with hematopoietic stem cell transplant]’, Umeda told Healio.’ Also, clarifying the background mechanism of AML with UBTF tandem duplication should provide a better understanding of how to overcome the dismal outcome of this subtype with current treatment strategies.”