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UBTF tandem duplications define a distinct subtype of adult de novo acute myeloid leukemia.

ABSTRACT: Tandem duplications (TDs) of the UBTF gene have been recently described as a recurrent alteration in pediatric acute myeloid leukemia (AML). Here, by screening 1946 newly diagnosed adult AML, we found that UBTF-TDs occur in about 3% of patients aged 18-60 years, in a mutually exclusive pattern with other known AML subtype-defining alterations. The characteristics of 59 adults with UBTF-TD AML included young age (median 37 years), low bone marrow (BM) blast infiltration (median 25%), and high rates of WT1 mutations (61%), FLT3-ITDs (51%) and trisomy 8 (29%). BM morphology frequently demonstrates dysmyelopoiesis albeit modulated by the co-occurrence of FLT3-ITD. UBTF-TD patients have lower complete remission (CR) rates (57% after 1 course and 76% after 2 courses of intensive chemotherapy [ICT]) than UBTF-wild-type patients. In patients enrolled in the ALFA-0702 study (n = 614 patients including 21 with UBTF-TD AML), the 3-year disease-free survival (DFS) and overall survival of UBTF-TD patients were 42.9% (95%CI: 23.4-78.5%) and 57.1% (95%CI: 39.5-82.8%) and did not significantly differ from those of ELN 2022 intermediate/adverse risk patients. Finally, the study of paired diagnosis and relapsed/refractory AML samples suggests that WT1-mutated clones are frequently selected under ICT. This study supports the recognition of UBTF-TD AML as a new AML entity in adults.

SUBMITTER: Duployez N

PROVIDER: S-EPMC10244165 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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UBTF tandem duplications define a distinct subtype of adult de novo acute myeloid leukemia.

Duployez Nicolas N Vasseur Loïc L Kim Rathana R Largeaud Laëtitia L Passet Marie M L'Haridon Anaïs A Lemaire Pierre P Fenwarth Laurène L Geffroy Sandrine S Helevaut Nathalie N Celli-Lebras Karine K Adès Lionel L Lebon Delphine D Berthon Céline C Marceau-Renaut Alice A Cheok Meyling M Lambert Juliette J Récher Christian C Raffoux Emmanuel E Micol Jean-Baptiste JB Pigneux Arnaud A Gardin Claude C Delabesse Eric E Soulier Jean J Hunault Mathilde M Dombret Hervé H Itzykson Raphael R Clappier Emmanuelle E Preudhomme Claude C

Leukemia 20230421 6

Tandem duplications (TDs) of the UBTF gene have been recently described as a recurrent alteration in pediatric acute myeloid leukemia (AML). Here, by screening 1946 newly diagnosed adult AML, we found that UBTF-TDs occur in about 3% of patients aged 18-60 years, in a mutually exclusive pattern with other known AML subtype-defining alterations. The characteristics of 59 adults with UBTF-TD AML included young age (median 37 years), low bone marrow (BM) blast infiltration (median 25%), and high rat ...[more]

PMID: 37085611

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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.

Dataset Information

UBTF tandem duplications define a distinct subtype of adult de novo acute myeloid leukemia.

Publications

UBTF tandem duplications define a distinct subtype of adult de novo acute myeloid leukemia.

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