Researchers uncover new subtype of pediatric AML defined by UBTF tandem duplications
Click Here to Manage Email Alerts
Upstream binding transcription factor tandem duplications, or UBTF-TDs, identified through 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 ASH Annual Meeting and Exposition, shine a light on underrecognized alterations that will be crucial for future risk-stratification of pediatric AML, according to the investigators.
“AMLs with UBTF tandem duplications otherwise have been regarded as ‘no-driver cases’ or FLT3+ leukemia so far,” Masayuki Umeda, MD, postdoctoral research fellow in lab of Jeffery M. Klco, MD, PhD, in the department of pathology at St. Jude Children's Research Hospital, told Healio. “Identification of the driver alteration can lead to accurate risk-stratification depending on gene alteration or molecular-targeting therapy based on the molecular mechanism behind leukemogenesis.”
Relapse is common among children with AML, resulting in a poor prognosis and a 5-year survival rate of 68%. However, studies have not fully characterized the molecular basis leading to relapse in pediatric AML, according to researchers.
Umeda and colleagues used RNA sequencing, whole-genome sequencing and target-capture sequencing to perform integrated profiling of 136 cases of relapsed pediatric AML cases, in order to understand the genetic landscape of pediatric AML at relapse.
They identified not only well-characterized fusion oncoproteins, including those that involve 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 reported previously, and all within the cohort were heterozygous in-frame exon 13 tandem duplications.
To better detect UBTF-TD, the investigators applied a soft-clipped read-based screening method to RNA-sequencing data of 417 additional pediatric AMLs. This led to identification of 15 additional UBTF-TDs, many of which had never been reported.
UBTF-TD AMLs appeared common in early adolescence (median age, 12.6 years; range, 2.4-19.6), and about two-thirds of cases had either normal karyotype (n = 12) or trisomy (n = 7). Researchers frequently observed FLT3-ITD (44.4%) and WT1 mutations (40.7%) with UBTF-TDs, which were mutually exclusive from NUP98 and KMT2A rearrangements and other recurrent fusion oncoproteins.
Data of four cases at multiple AML time points suggested UBTF-TD is a clonal alteration, and analysis of transcriptome data showed 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 that UBTF-TD is a unique pediatric AML subtype, according to researchers.
High variant allele frequency at relapse and diagnosis showed UBTF-TD is a clonal event in leukemogenesis.
Further investigation of UBTF-TDs in cord blood CD34+ cells showed overexpression promotes colony-forming activity and cell growth, resulting in cells with a 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 lower prevalence in the BeatAML and TCGA cohorts. UBTF-TDs in the AAML1031 cohort remained mutually exclusive with known AML molecular subtypes of AML and often occurred 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 of AML with UBTF tandem duplication to decide how we should treat this subtype, including [with hematopoietic stem cell transplant],” Umeda told Healio.” Also, clarification of the background mechanism of AML with UBTF tandem duplication should provide better insight into how we should overcome the dismal outcome of this subtype with current treatment strategies.”
Collapse
Umeda M, et al. Abstract LBA-4. Presented at: ASH Annual Meeting and Exposition. Dec. 11-14, 2021; Atlanta.
Click Here to Manage Email Alerts