Two novel high-risk adult B-cell acute lymphoblastic leukemia subtypes with high expression of <i>CDX2</i> and <i>IDH1/2</i> mutations

Yasuda, Takahiko; Sanada, Masashi; Kawazu, Masahito; Kojima, Shinya; Tsuzuki, Shinobu; Ueno, Hikaru; Iwamoto, Eisuke; Iijima-Yamashita, Yuka; Yamada, Tomomi; Kanamori, Takashi; Nishimura, Rieko; Kuwatsuka, Yachiyo; Takada, Satoru; Tanaka, Masatsugu; Ota, Shuichi; Dobashi, Nobuaki; Yamazaki, Etsuko; Hirose, Asao; Murayama, Tohru; Sumi, Masahiko; Sato, Shinya; Tange, Naoyuki; Nakamura, Yukinori; Katsuoka, Yoji; Sakaida, Emiko; Kawamata, Toyotaka; Iida, Hiroatsu; Shiraishi, Yuichi; Nannya, Yasuhito; Ogawa, Seishi; Asou, Norio; Hatta, Yoshihiro; Kiyoi, Hitoshi; Matsumura, Itaru; Horibe, Keizo; Mano, Hiroyuki; Naoe, Tomoki; Miyazaki, Yasushi; Hayakawa, Fumihiko

doi:10.1182/blood.2021011921

Cited by 31 publications

(51 citation statements)

References 49 publications

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“…A poor prognosis was also reported in Yasuda et al, with lower disease-free and overall survival. 38 By contrast, OS of CDX2/UBTF ALL was not lower in the present study, likely because of efficient salvage therapies currently available. Overall, our study reveals a novel high-risk B-ALL subtype, which requires novel therapeutic developments.…”

Section: Discussioncontrasting

confidence: 65%

“…Third, the pattern of additional genomic alterations exhibited several notable features. They comprised a number of large chromosomal imbalances, including recurrent duplications in 1q arm, also observed by Yasuda et al, 38 and deletions in 3q, 6q, 9q, and 13q, which is not common in B-ALL and suggests underlying genomic instability. Of note, CDX2 has been previously involved in inhibition of DNA double-strand break repair activity in intestinal context.…”

Section: Discussionmentioning

confidence: 70%

“…Our study, demonstrating the targeting and strong deregulation of CDX2 by a recurrent alteration in a subset of B-ALL, thus provides definitive support for its oncogenic role in human leukemia. A recent article from Yasuda et al 38 reported the CDX2-expressing B-ALL subtype but did not elucidate the mechanism of its deregulation. Interestingly, we uncovered focal alterations within the CDX2-FLT3-PAN3 locus in all CDX2/UBTF ALL patients and in the NALM16 cell line and proved CDX2 cis -deregulation mediated by enhancer hijacking.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussioncontrasting

confidence: 65%

Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

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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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“…Genetic abnormalities that have attracted attention in recent years were not included in this study. [53][54][55][56] For example, although Ph-like ALL has been established as a non-Ph subset with a poor prognosis, 57 Ph-like ALL could not be identified in the TRUMP database. In the near future, it will be necessary to plan a treatment strategy that considers genetic abnormalities, and an analysis of allo-HCT for ALL that includes genetic abnormalities as covariates is warranted.…”

Section: Discussionmentioning

confidence: 99%

Improvements in allogeneic hematopoietic cell transplantation outcomes for adults with ALL over the past 3 decades

et al. 2022

Self Cite

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Allogeneic hematopoietic cell transplantation (allo-HCT) is a promising treatment for adult acute lymphoblastic leukemia (ALL), an intractable hematological malignancy. The trends in allo-HCT outcomes over the past 30 years were examined to verify the efficacy of evolving treatment methods and to identify further challenges. We analyzed data from a registry database that included 8467 adult ALL patients who underwent their first allo-HCT between 1990 and 2019. The period was divided into three 10-year intervals for analysis. Five-year overall survival improved from 48.2% to 70.2% in the first complete remission (CR1), from 25.6% to 44.1% in subsequent CR, and from 10.0% to 22.7% in non-CR. Non-relapse mortality improved over the 3 decades in each disease stage. However, the relapse rate only improved in CR1 every decade (26.3% to 15.9% in CR1, 33.4% to 32.8% in subsequent CR, and 53.6% to 54.8% in non-CR). Although there was continual improvements in adjusted survival for Philadelphia-chromosome (Ph) positive patients, the improvement was inadequate for Ph negative patients with t(4;11), t(8;14), t(14;18), or hypodiploidy. Allo-HCT outcomes for adults with ALL have improved over the past 30 years. Improved outcomes in the future will require more effective prevention of relapse in patients with ALL not in CR1 and in those with high-risk chromosomal abnormalities.

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“…In the text, we use the term ‘genomic ALL subtype’ when the subtype is assigned according to a DNA or RNA sequence abnormality or a clinical biomarker independently of gene expression levels. The detection of genomic alterations and subsequent subtyping of ALL cases were based on the previously published analyses of the North American samples [12] and a preliminary definition of a recently discovered rare CDX2 subtype [38]. We were not able to define the DUX4 subtype independently of mRNA expression levels due to its cryptic nature.…”

Section: Methodsmentioning

confidence: 99%

Multi-cohort transcriptomic subtyping of B-cell acute lymphoblastic leukemia

Mäkinen

Rehn

Breen

et al. 2022

Preprint

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Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and comprises multiple genetically distinguishable subtypes. To detect subtypes, current pipelines include fusion calling, polymorphisms, candidate gene copy numbers and cytogenetics but these approaches have limitations. RNA-seq provides a functional genome-wide snapshot that enables classification of ALL subtypes, however, typical mRNA-seq clustering analyses lack the rigor of quantitative modelling. Furthermore, high-dimensional gene expression data across cohorts and countries come with biases that previous transcriptomics studies have not addressed. Our aim was to integrate easy-to-interpret reliable transcriptome-wide biomarkers into subtyping pipelines. We analyzed 2,046 samples from two continents, carefully adjusted for biases, and applied a rigorous machine learning design with independent replication. Six ALL subtypes that covered 32% of patients were robustly detected by mRNA-seq (PPV ≥ 87%). Five other frequent subtypes were distinguishable in 40% of patients, although overlapping transcriptional profiles led to lower accuracy (52% ≤ PPV ≤ 73%). Based on these findings, we developed the Allspice tool that predicts ALL subtypes and driver genes from unadjusted mRNA-seq read counts as encountered in real-world settings. Allspice also includes quantitative classification and safety metrics to help determine the most plausible genetic drivers for cases where other findings are inconclusive.

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Two novel high-risk adult B-cell acute lymphoblastic leukemia subtypes with high expression of CDX2 and IDH1/2 mutations

Cited by 31 publications

References 49 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

Improvements in allogeneic hematopoietic cell transplantation outcomes for adults with ALL over the past 3 decades

Multi-cohort transcriptomic subtyping of B-cell acute lymphoblastic leukemia

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