Integrated Genomic Analysis Identifies <i>UBTF</i> Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia

Umeda, Mikio; Ma, Jing; Huang, Benjamin; Hagiwara, Kohei; Westover, Tamara; Abdelhamed, Sherif; Barajas, Juan M.; Thomas, Melvin E.; Walsh, Michael P.; Song, Guangchun; Tian, Liqing; Liu, Yanling; Chen, Xiaolong; Kolekar, Pandurang; Tran, Quang; Foy, Scott G.; Maciaszek, Jamie L.; Kleist, Andrew B.; Leonti, Amanda R.; Ju, Bensheng; Easton, John; Wu, Huiyun; Valentine, Virginia; Valentine, Marcus B.; Liu, Yen-Chun; Ries, Rhonda E.; Smith, Jenny L.; Parganas, Evan; Iacobucci, Ilaria; Hiltenbrand, Ryan; Miller, Jonathan; Myers, Jason R.; Rampersaud, Evadnie; Rahbarinia, Delaram; Rusch, Michael; Wu, Gang; Inaba, Hiroto; Wang, Yicheng; Alonzo, Todd A.; Downing, James R.; Mullighan, Charles G.; Pounds, Stanley; Babu, M. Madan; Zhang, Jinghui; Rubnitz, Jeffrey E.; Meshinchi, Soheil; Ma, Xiaotu; Klco, Jeffery M.

doi:10.1158/2643-3230.bcd-21-0160

Cited by 59 publications

(129 citation statements)

References 70 publications

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“…In addition, tandem duplication of UBTF was recently reported in pediatric AML. 29,30 The predicted UBTF::ATXN7L3 fusion protein retained the major part of UBTF, including all high mobility group box domains and the entire ATXN7L3. Western blot analysis confirmed the presence of an ATXN7L3-containing protein at the expected size in cases harboring the alteration ( Figure 1F ).…”

Section: Resultsmentioning

confidence: 94%

“… 42 Interestingly, alterations targeting UBTF (ie, internal tandem duplications) were reported as a recurrent lesion in pediatric AML. 29,30 Because it is ubiquitously expressed and interacts with DNA as a dimer, its role in the fusion may also fit with the common model for chimeric fusions where the 5′ partner allows deregulated expression and dimerization of the 3′ partner, altering its properties of DNA binding or cofactors recruitment. 43 …”

Section: Discussionmentioning

confidence: 97%

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Concurrent CDX2 cis-deregulation and UBTF::ATXN7L3 fusion define a novel high-risk subtype of B-cell ALL

Passet

Kim

Gachet

et al. 2022

Blood

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Oncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA-seq and whole-genome analyses in a large cohort of unresolved B-ALL. We identified a novel subtype characterized by a distinct gene expression signature and the unique association of two genomic microdeletions. The 17q21.31 microdeletion resulted in a UBTF::ATXN7L3 fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2, located 138 kb in cis from the deletion. Using 4C-seq and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3 enhancer hijacking. CDX2/UBTF ALL (n=26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4 activating mutations. Within adult patients with Ph-negative B-ALL enrolled in GRAALL trials, patients with CDX2/UBTF ALL (n=17/723, 2.4%) were frequently young women (M/F ratio 0.2, P=0.002, median age 31 years). They commonly presented with a pro-B phenotype ALL and moderate blast cell infiltration. They had poor response to treatment including a higher risk of failure to first induction course (19% versus 3%, P=0.017) and higher post-induction MRD levels (MRD ≥ 10-4, 93%, versus 46%, P<0.001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% versus 32.4%, P=0.004) in univariate and multivariate analyses. In conclusion, we discovered a novel B-ALL entity defined by the unique combination of CDX2 cis-deregulation and UBTF::ATXN7L3 fusion, representing a high-risk disease in young adults. Study can be found on https://clinicaltrials.gov NCT00327678 and NCT02617004.

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Section: Resultsmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 97%

Concurrent CDX2 cis-deregulation and UBTF::ATXN7L3 fusion define a novel high-risk subtype of B-cell ALL

Passet

Kim

Gachet

et al. 2022

Blood

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“…[21][22][23] The fusion involving UBTF-ATXN7L3 results from a 17q21.31 microdeletion between exon 17 of UBTF and exon 1 of tandem duplication was recurrently identified in pediatric AML, and this alteration may represent a novel subtype-defining lesion. 51 Although the molecular mechanism for B-ALL development of this subtype is poorly understood, defining a close relationship between this group and two universal genomic deletions (13q and 17q deletion) provides us with a hint about a leukemogenic process that may be driven by cooperative effects of the UBTF-ATXN7L3 fusion protein and CDX2 deregulation (Table 1).…”

Section: Cdx2/ubtf Allmentioning

confidence: 99%

Oncogenic lesions and molecular subtypes in adults with B‐cell acute lymphoblastic leukemia

et al. 2022

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B‐cell acute lymphoblastic leukemia (B‐ALL), a genetically heterogeneous disease, is classified into different molecular subtypes that are defined by recurrent gene rearrangements, gross chromosomal abnormalities, or specific gene mutations. Cells with these genetic alterations acquire a leukemia‐initiating ability and show unique expression profiles. The distribution of B‐ALL molecular subtypes is greatly dependent on age, which also affects treatment responsiveness and long‐term survival, partly accounting for the inferior outcome in adolescents and young adults (AYA) and (older) adults with B‐ALL. Recent advances in sequencing technology, especially RNA sequencing and the application of these technologies in large B‐ALL cohorts have uncovered B‐ALL molecular subtypes prevalent in AYA and adults. These new insights supply more precise estimations of prognoses and targeted therapies informed by sequencing results, as well as a deeper understanding of the genetic basis of AYA/adult B‐ALL. This article provides an account of these technological advances and an overview of the recent major findings of B‐ALL molecular subtypes in adults.

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“…In this issue of Blood Cancer Discovery, Dr Masayuki Umeda and colleagues studied a series of relapsed pediatric AML cases using intensive genomic analysis and identified a previously rarely described genomic alteration, UBTF tandem duplications (UBTF-TD), in a large subset (8.8%) of cases (7). Through interrogation of larger de novo pediatric and adult AML cohorts, they identified UBTF-TD in 4% of pediatric AMLs.…”

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confidence: 99%

Bedside to Bench and Back: Identifying a New Clinically Relevant Driver in Pediatric Acute Myeloid Leukemia

Nardi

2022

Blood Cancer Discovery

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In this issue of Blood Cancer Discovery, Dr Masayuki Umeda and colleagues identify and comprehensively analyze a novel recurrent UBTF mutation (tandem duplications) in pediatric acute myeloid leukemia. Acute myeloid leukemia cases with UBTF tandem duplications display distinctive biologic features, including association with FLT3-ITD and WT1 mutations and high-risk disease, and appear to represent a new genetic subtype of acute myeloid leukemia.

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

Cited by 59 publications

References 70 publications

Concurrent CDX2 cis-deregulation and UBTF::ATXN7L3 fusion define a novel high-risk subtype of B-cell ALL

Concurrent CDX2 cis-deregulation and UBTF::ATXN7L3 fusion define a novel high-risk subtype of B-cell ALL

Oncogenic lesions and molecular subtypes in adults with B‐cell acute lymphoblastic leukemia

Bedside to Bench and Back: Identifying a New Clinically Relevant Driver in Pediatric Acute Myeloid Leukemia

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