Tandem Duplications of the <i>UBTF</i> gene in Adult AML: A Rare but Recurrent Alteration Associated with Myelodysplasia and Poor Outcome

Georgi, Julia-Annabell; Stasik, Sebastian; Hartwig, Marita; Röllig, Christoph; Oelschlaegel, Uta; Krug, Utz; Sauer, Tim; Scholl, Sebastian; Hochhaus, Andreas; Brümmendorf, Tim H.; Naumann, Ralph; Steffen, Björn; Einsele, Hermann; Schaich, Markus; Burchert, Andreas; Neubauer, Andreas; Schaefer-Eckart, Kerstin; Schliemann, Christoph; Krause, Stefan W.; Haenel, Mathias; Noppeney, Richard; Kaiser, Ulrich; Baldus, Claudia D.; Kaufmann, Martin; Müller‐Tidow, Carsten; Platzbecker, Uwe; Berdel, Wolfgang E.; Ehninger, Gerhard; Bornhaeuser, Martin; Schetelig, Johannes; Kroschinsky, Frank; Thiede, Christian

doi:10.1182/blood-2022-164702

“…We and others have previously shown that AML with UBTF -TD is characterized by high HOXA and HOXB cluster gene expression, similar to NPM1 -mutated or NUP98 :: NSD1 AML (1, 4, 8). To further define the unique expression profiles of UBTF- TD, we established an RNA-seq cohort consisting of various AML subtypes (1) (n=837), cord blood CD34+ samples from healthy donors (n=5), and UBTF- TD AML and MDS samples (n=94: 1 UBTF- TD case did not have RNA-seq data available) ( Figure 4A ).…”

Section: Resultsmentioning

confidence: 71%

UBTFTandem Duplications in Pediatric MDS and AML: Implications for Clinical Screening and Diagnosis

Barajas,

Umeda,

Contreras

et al. 2023

Preprint

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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 ofUBTF-TD myeloid neoplasms in childhood, including 89 unique pediatric AML and 6 myelodysplastic syndrome (MDS) cases harboring a tandem duplication in exon 13 ofUBTF. We demonstrate thatUBTF-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 thatUBTF-TD is an early and clonal event associated with a distinct transcriptional profile, whereas the acquisition ofFLT3orWT1mutations is associated with more stem cell-like programs. Lastly, we report rare duplications within exon 9 ofUBTFthat phenocopy exon 13 duplications, expanding the spectrum ofUBTFalterations in pediatric myeloid tumors. Collectively, we comprehensively characterize pediatric AML and MDS withUBTF-TD and highlight key clinical and pathologic features that distinguish this new entity from other molecular subtypes of AML.Key PointsLargest cohort of pediatricUBTF-TD in myeloid neoplasms reported to date.Use of single-cell DNA+protein sequencing technology in 3UBTF-TD samples reveals a clonal evaluation pattern characterized by sequential acquisition ofWT1andFLT3mutations and a more stem cell-like protein expression pattern.Pediatric MDS and AML patients withUBTF-TD alterations dysplastic features with an increase erythroid precursors.Tandem duplications in exon 9 ofUBTFrepresent a rare but functionally equivalent subgroup ofUBTF-TD myeloid neoplasms.Impact StatementUBTFtandem duplications (TD) are subtype-defining genomic alterations in adult and pediatric myeloid neoplasms. Here, we provide a comprehensive characterization of the largest cohort of pediatricUBTF-TD cases to date, including the recognition of additional UBTF alterations that mimic the exon 13 duplications in pediatric AML.

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“…Myelodysplasia-related chromosomal changes or myelodysplasia-related mutations were overall rare, suggesting that UBTF-TD itself contributes to dysplastic features (Supplemental Table 5). Considering these overall features and other recent publications (5,8,9,22,23), the majority of UBTF-TD AMLs (83/89, 93.3%) are best classified as "Acute myeloid leukemia with other defined genetic alterations" in the current WHO classification (20) (Supplemental Table 5).…”

Section: Clinical Features Of Ubtf-td Pediatric Myeloid Neoplasmsmentioning

confidence: 78%

“…Recurrent tandem duplications (TD) of exon 13 of upstream binding transcription factor (UBTF) were only recently identified as potential initiating events in pediatric AML (4-7), accounting for about 4% of newly diagnosed pediatric AML. PCR-based screening covering exon 13 of UBTF also identified UBTF-TD alterations in large adult AML cohorts (8,9). These studies significantly contributed to the accumulation of evidence of UBTF-TD alterations in adult AML.…”

Section: Introductionmentioning

confidence: 82%

“…We and others have previously shown that AML with UBTF-TD is characterized by high HOXA and HOXB cluster gene expression, similar to NPM1-mutated or NUP98::NSD1 AML (1,8). To further define the unique expression profiles of UBTF-TD, we established an RNA-seq cohort consisting of various AML subtypes (1) (n=837), cord blood CD34+ samples from healthy donors (n=5), and UBTF-TD AML and MDS samples (n=94: 1 UBTF-TD case did not have RNA-seq data available) (Figure 4A).…”

Section: Transcriptional Features Of Ubtf-td Myeloid Neoplasmsmentioning

confidence: 94%

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<i>UBTF</i> tandem duplications in pediatric myelodysplastic syndrome and acute myeloid leukemia: implications for clinical screening and diagnosis

Barajas,

Umeda,

Contreras

et al. 2024

haematol

0

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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 about 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 celllike 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.

show abstract

“…1,2 These cases appear mutually exclusive with other subtype-defining lesions in AML and display distinct clinicopathologic features: cytogenetics often identifies either a normal karyotype or trisomy 8, and co-mutations in FLT3 and WT1 are common. 1,3 Clinically, UBTF-TD AMLs are associated with inferior outcomes compared to UBTF wild-type cases, with lower complete remission rates and a higher incidence of measurable residual disease (MRD) positivity after induction therapy. [1][2][3] Therefore, comprehensive laboratory evaluation at diagnosis and subsequent MRD assessment timepoints will be critical for patient risk stratification and guiding potential adapted therapeutic strategies.…”

Section: Immunophenotypic Characterisation Of Acute Myeloid Leukaemia...mentioning

confidence: 99%

Immunophenotypic characterisation of acute myeloid leukaemia with UBTF tandem duplications

Harrop,

Nguyen,

Robinson

et al. 2024

Br J Haematol

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Tandem Duplications of the UBTF gene in Adult AML: A Rare but Recurrent Alteration Associated with Myelodysplasia and Poor Outcome

Cited by 3 publications

References 0 publications

UBTFTandem Duplications in Pediatric MDS and AML: Implications for Clinical Screening and Diagnosis

UBTFTandem Duplications in Pediatric MDS and AML: Implications for Clinical Screening and Diagnosis

<i>UBTF</i> tandem duplications in pediatric myelodysplastic syndrome and acute myeloid leukemia: implications for clinical screening and diagnosis

Immunophenotypic characterisation of acute myeloid leukaemia with UBTF tandem duplications

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