Dataset Information

Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia.

ABSTRACT: The genetics of relapsed pediatric acute myeloid leukemia (AML) has yet to be comprehensively defined. Here, we present the spectrum of genomic alterations in 136 relapsed pediatric AMLs. We identified recurrent exon 13 tandem duplications (TD) in upstream binding transcription factor (UBTF) in 9% of relapsed AML cases. UBTF-TD AMLs commonly have normal karyotype or trisomy 8 with cooccurring WT1 mutations or FLT3-ITD but not other known oncogenic fusions. These UBTF-TD events are stable during disease progression and are present in the founding clone. In addition, we observed that UBTF-TD AMLs account for approximately 4% of all de novo pediatric AMLs, are less common in adults, and are associated with poor outcomes and MRD positivity. Expression of UBTF-TD in primary hematopoietic cells is sufficient to enhance serial clonogenic activity and to drive a similar transcriptional program to UBTF-TD AMLs. Collectively, these clinical, genomic, and functional data establish UBTF-TD as a new recurrent mutation in AML.

Significance

We defined the spectrum of mutations in relapsed pediatric AML and identified UBTF-TDs as a new recurrent genetic alteration. These duplications are more common in children and define a group of AMLs with intermediate-risk cytogenetic abnormalities, FLT3-ITD and WT1 alterations, and are associated with poor outcomes. See related commentary by Hasserjian and Nardi, p. 173. This article is highlighted in the In This Issue feature, p. 171.

SUBMITTER: Umeda M

PROVIDER: S-EPMC9780084 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia.

Umeda Masayuki M Ma Jing J Huang Benjamin J BJ Hagiwara Kohei K Westover Tamara T Abdelhamed Sherif S Barajas Juan M JM Thomas Melvin E ME Walsh Michael P MP Song Guangchun G Tian Liqing L Liu Yanling Y Chen Xiaolong X Kolekar Pandurang P Tran Quang Q Foy Scott G SG Maciaszek Jamie L JL Kleist Andrew B AB Leonti Amanda R AR Ju Bengsheng B Easton John J Wu Huiyun H Valentine Virginia V Valentine Marcus B MB Liu Yen-Chun YC Ries Rhonda E RE Smith Jenny L JL Parganas Evan E Iacobucci Ilaria I Hiltenbrand Ryan R Miller Jonathan J Myers Jason R JR Rampersaud Evadnie E Rahbarinia Delaram D Rusch Michael M Wu Gang G Inaba Hiroto H Wang Yi-Cheng YC Alonzo Todd A TA Downing James R JR Mullighan Charles G CG Pounds Stanley S Babu M Madan MM Zhang Jinghui J Rubnitz Jeffrey E JE Meshinchi Soheil S Ma Xiaotu X Klco Jeffery M JM

Blood cancer discovery 20220501 3

The genetics of relapsed pediatric acute myeloid leukemia (AML) has yet to be comprehensively defined. Here, we present the spectrum of genomic alterations in 136 relapsed pediatric AMLs. We identified recurrent exon 13 tandem duplications (TD) in upstream binding transcription factor (UBTF) in 9% of relapsed AML cases. UBTF-TD AMLs commonly have normal karyotype or trisomy 8 with cooccurring WT1 mutations or FLT3-ITD but not other known oncogenic fusions. These UBTF-TD events are stable during ...[more]

PMID: 35176137

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Project description:Recent genomic studies in adult and pediatric acute myeloid leukemia (AML) demonstrated recurrent in-frame tandem duplications (TD) in exon 13 of upstream binding transcription factor ( UBTF ). These alterations, which account for ~4.3% of AMLs in childhood and up to 3% in adult AMLs under 60, are subtype-defining and associated with poor outcomes. Here, we provide a comprehensive investigation into the clinicopathological features of UBTF -TD myeloid neoplasms in childhood, including 89 unique pediatric AML and 6 myelodysplastic syndrome (MDS) cases harboring a tandem duplication in exon 13 of UBTF . We demonstrate that UBTF- TD myeloid tumors are associated with dysplastic features, low bone marrow blast infiltration, and low white blood cell count. Furthermore, using bulk and single-cell analyses, we confirm that UBTF -TD is an early and clonal event associated with a distinct transcriptional profile, whereas the acquisition of FLT3 or WT1 mutations is associated with more stem cell-like programs. Lastly, we report rare duplications within exon 9 of UBTF that phenocopy exon 13 duplications, expanding the spectrum of UBTF alterations in pediatric myeloid tumors. Collectively, we comprehensively characterize pediatric AML and MDS with UBTF- TD and highlight key clinical and pathologic features that distinguish this new entity from other molecular subtypes of AML.Key pointsLargest cohort of pediatric UBTF- TD in myeloid neoplasms reported to date. Use of single-cell DNA+protein sequencing technology in 3 UBTF- TD samples reveals a clonal evaluation pattern characterized by sequential acquisition of WT1 and FLT3 mutations and a more stem cell-like protein expression pattern. Pediatric MDS and AML patients with UBTF- TD alterations dysplastic features with an increase erythroid precursors. Tandem duplications in exon 9 of UBTF represent a rare but functionally equivalent subgroup of UBTF- TD myeloid neoplasms.Impact statementUBTF tandem duplications (TD) are subtype-defining genomic alterations in adult and pediatric myeloid neoplasms. Here, we provide a comprehensive characterization of the largest cohort of pediatric UBTF -TD cases to date, including the recognition of additional UBTF alterations that mimic the exon 13 duplications in pediatric AML.

Project description:Tandem-duplication mutations of the UBTF gene (UBTF-TDs) coding for the upstream binding transcription factor have recently been described in pediatric patients with acute myeloid leukemia (AML) and were found to be associated with particular genetics (trisomy 8 (+8), FLT3-internal tandem duplications (FLT3-ITD), WT1-mutations) and inferior outcome. Due to limited knowledge on UBTF-TDs in adult AML, we screened 4247 newly diagnosed adult AML and higher-risk myelodysplastic syndrome (MDS) patients using high-resolution fragment analysis. UBTF-TDs were overall rare (n = 52/4247; 1.2%), but significantly enriched in younger patients (median age 41 years) and associated with MDS-related morphology as well as significantly lower hemoglobin and platelet levels. Patients with UBTF-TDs had significantly higher rates of +8 (34% vs. 9%), WT1 (52% vs. 7%) and FLT3-ITD (50% vs. 20.8%) co-mutations, whereas UBTF-TDs were mutually exclusive with several class-defining lesions such as mutant NPM1, in-frame CEBPAbZIP mutations as well as t(8;21). Based on the high-variant allele frequency found and the fact that all relapsed patients analyzed (n = 5) retained the UBTF-TD mutation, UBTF-TDs represent early clonal events and are stable over the disease course. In univariate analysis, UBTF-TDs did not represent a significant factor for overall or relapse-free survival in the entire cohort. However, in patients under 50 years of age, who represent the majority of UBTF-mutant patients, UBTF-TDs were an independent prognostic factor for inferior event-free (EFS), relapse-free (RFS) and overall survival (OS), which was confirmed by multivariable analyses including established risk factors such as age and ELN2022 genetic risk groups (EFS [HR: 2.20; 95% CI 1.52-3.17, p < 0.001], RFS [HR: 1.59; 95% CI 1.02-2.46, p = 0.039] and OS [HR: 1.64; 95% CI 1.08-2.49, p = 0.020]). In summary, UBTF-TDs appear to represent a novel class-defining lesion not only in pediatric AML but also younger adults and are associated with myelodysplasia and inferior outcome in these patients.

Dataset Information

Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia.

Significance

Publications

Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia.

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