Comprehensive characterization of a novel, oncogenic and targetable <scp>SEPTIN6</scp>::<scp>ABL2</scp> fusion in <scp>T‐ALL</scp>

Lahera, Antonio; Vela‐Martín, Laura; López-Nieva, Pilar; Salgado, Rocío; Rodríguez-Perales, Sandra; Torres-Ruíz, Raúl; López-Lorenzo, José Luis; Cornago, Javier; Llamas, Pilar; Fernández-Navarro, Pablo; Sanchez-Dominguez, Rebeca; Segovia, José C.; Sastre, Isabel; Cobos-Fernández, María Ángeles; Menéndez, Pablo; Santos, Javíer; Fernández‐Piqueras, José; Villa‐Morales, María

doi:10.1111/bjh.18901

Cited by 3 publications

(4 citation statements)

References 14 publications

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“…Interestingly, we found SEPTIN6 :: ABL2 fusion in a cortical T-ALL case. This has been recently described in a T-ALL case at diagnosis and relapse ( 79 ). This fusion was shown to have oncogenic potential and responded to TKI highlighting the fact that this fusion oncoprotein can be used as therapeutic target in T-ALL ( 79 ).…”

Section: Discussionmentioning

confidence: 72%

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Decoding the genetic symphony: Profiling protein-coding and long noncoding RNA expression in T-acute lymphoblastic leukemia for clinical insights

Verma,

Kapoor,

Kumari

et al. 2024

PNAS Nexus

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T-acute lymphoblastic leukemia (T-ALL) is a heterogeneous malignancy characterized by the abnormal proliferation of immature T-cell precursors. Despite advances in immunophenotypic classification, understanding the molecular landscape and its impact on patient prognosis remains challenging. In this study, we conducted comprehensive RNA sequencing in a cohort of 35 T-ALL patients to unravel the intricate transcriptomic profile. Subsequently, we validated the prognostic relevance of 23 targets, encompassing (i) Protein-coding genes - BAALC, HHEX, MEF2C, FAT1, LYL1, LMO2, LYN, and TAL1; (ii) Epigenetic modifiers - DOT1L, EP300, EML4, RAG1, EZH2, and KDM6A; and (iii) long non-coding RNAs (lncRNAs) - XIST, PCAT18, PCAT14, LINC00202, LINC00461, LINC00648, ST20, MEF2C-AS1, and MALAT1 in an independent cohort of 99 T-ALL patients. Principal component analysis revealed distinct clusters aligning with immunophenotypic subtypes, providing insights into the molecular heterogeneity of T-ALL. The identified signature genes exhibited associations with clinicopathologic features. Survival analysis uncovered several independent predictors of patient outcomes. Higher expression of MEF2C, BAALC, HHEX, and LYL1 genes emerged as robust indicators of poor overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS). Higher LMO2 expression correlated with adverse EFS and RFS outcomes. Intriguingly, increased expression of lncRNA ST20 coupled with RAG1, demonstrated a favorable prognostic impact on OS, EFS, and RFS. Conclusively, several novel associations of gene expression patterns with clinicopathological features and prognosis were identified, which may help understand T-ALL's molecular pathogenesis and provide novel prognostic markers.

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Section: Discussionmentioning

confidence: 72%

“…This has been recently described in a T-ALL case at diagnosis and relapse ( 79 ). This fusion was shown to have oncogenic potential and responded to TKI highlighting the fact that this fusion oncoprotein can be used as therapeutic target in T-ALL ( 79 ). We found CRLF2 :: IGH fusion in a case with cortical immunophenotype.…”

Section: Discussionmentioning

confidence: 72%

Decoding the genetic symphony: Profiling protein-coding and long noncoding RNA expression in T-acute lymphoblastic leukemia for clinical insights

Verma,

Kapoor,

Kumari

et al. 2024

PNAS Nexus

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“…Likewise on chromosome 12, expression of Matn3, Osr1, and Nt5c1b have been associated with colon adenocarcinoma, gastric and breast cancer development ( Zhao Z. et al, 2023a ; Chi et al, 2023 ; Gadwal et al, 2023 ); potential use as a biomarker for breast cancer ( Li et al, 2020 ) or promotion of EMT and metastasis in breast cancer ( Wang et al, 2020 ; Li et al, 2021 ) and identified as a cancer testis-antigen in canine malignancies ( Nemec et al, 2019 ) respectively. On the X chromosome, Il13ra1, Pgrmc1, Septin6, Ndufa1, Nkrf, Zcchc12, Lonrf3, Slc25a5, Ct47 and Dock11 have been associated with numerous cancers including: breast cancer ( Park et al, 2017 ; Zhao Y. et al, 2023 ), basal cell carcinoma ( Mamelak et al, 2005 ), glioblastoma multiforme ( Han and Puri, 2018 ), gastric cancer ( Li et al, 2019 ), hepatocellular carcinoma ( Fan et al, 2021 ), lung cancer ( Lu et al, 2023 ), neuroblastoma ( Seneviratne et al, 2023 ), osteosarcoma ( Cui and Dong, 2022 ), ovarian serous cystadenocarcinoma ( Zhang et al, 2018 ), pancreatic cancer ( Feng et al, 2021 ; Shi et al, 2022 ), papillary thyroid cancer ( Wang et al, 2017 ) and T-cell acute lymphoblastic leukemia ( Lahera et al, 2023 ). Whereas members of the A kinase anchor (AKAP) and Reproductive homeobox (Rhox) protein families are associated with various cancers ( MacLean, 2013 ; Reggi and Diviani, 2017 ; Vaughan-Shaw et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Frontiers in Toxicology frontiersin.org 15 carcinoma (Mamelak et al, 2005), glioblastoma multiforme (Han and Puri, 2018), gastric cancer (Li et al, 2019), hepatocellular carcinoma (Fan et al, 2021), lung cancer (Lu et al, 2023), neuroblastoma (Seneviratne et al, 2023), osteosarcoma (Cui and Dong, 2022), ovarian serous cystadenocarcinoma (Zhang et al, 2018), pancreatic cancer (Feng et al, 2021;Shi et al, 2022), papillary thyroid cancer (Wang et al, 2017) and T-cell acute lymphoblastic leukemia (Lahera et al, 2023). Whereas members of the A kinase anchor (AKAP) and Reproductive homeobox (Rhox) protein families are associated with various cancers (MacLean, 2013;Reggi and Diviani, 2017;Vaughan-Shaw et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

The MexTAg collaborative cross: host genetics affects asbestos related disease latency, but has little influence once tumours develop

Fisher,

Patrick,

Hoang

et al. 2024

Front. Toxicol.

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Objectives: This study combines two innovative mouse models in a major gene discovery project to assess the influence of host genetics on asbestos related disease (ARD). Conventional genetics studies provided evidence that some susceptibility to mesothelioma is genetic. However, the identification of host modifier genes, the roles they may play, and whether they contribute to disease susceptibility remain unknown. Here we report a study designed to rapidly identify genes associated with mesothelioma susceptibility by combining the Collaborative Cross (CC) resource with the well-characterised MexTAg mesothelioma mouse model.Methods: The CC is a powerful mouse resource that harnesses over 90% of common genetic variation in the mouse species, allowing rapid identification of genes mediating complex traits. MexTAg mice rapidly, uniformly, and predictably develop mesothelioma, but only after asbestos exposure. To assess the influence of host genetics on ARD, we crossed 72 genetically distinct CC mouse strains with MexTAg mice and exposed the resulting CC-MexTAg (CCMT) progeny to asbestos and monitored them for traits including overall survival, the time to ARD onset (latency), the time between ARD onset and euthanasia (disease progression) and ascites volume. We identified phenotype-specific modifier genes associated with these traits and we validated the role of human orthologues in asbestos-induced carcinogenesis using human mesothelioma datasets.Results: We generated 72 genetically distinct CCMT strains and exposed their progeny (2,562 in total) to asbestos. Reflecting the genetic diversity of the CC, there was considerable variation in overall survival and disease latency. Surprisingly, however, there was no variation in disease progression, demonstrating that host genetic factors do have a significant influence during disease latency but have a limited role once disease is established. Quantitative trait loci (QTL) affecting ARD survival/latency were identified on chromosomes 6, 12 and X. Of the 97-protein coding candidate modifier genes that spanned these QTL, eight genes (CPED1, ORS1, NDUFA1, HS1BP3, IL13RA1, LSM8, TES and TSPAN12) were found to significantly affect outcome in both CCMT and human mesothelioma datasets.Conclusion: Host genetic factors affect susceptibility to development of asbestos associated disease. However, following mesothelioma establishment, genetic variation in molecular or immunological mechanisms did not affect disease progression. Identification of multiple candidate modifier genes and their human homologues with known associations in other advanced stage or metastatic cancers highlights the complexity of ARD and may provide a pathway to identify novel therapeutic targets.

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Sustained long-term remission with tyrosine kinase inhibitor therapy in treatment-refractory B-cell acute lymphoblastic leukemia harboring a RCSD1::ABL2 fusion gene

Zahid,

Kainthla

2023

Leukemia & Lymphoma

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Comprehensive characterization of a novel, oncogenic and targetable SEPTIN6::ABL2 fusion in T‐ALL

Cited by 3 publications

References 14 publications

Decoding the genetic symphony: Profiling protein-coding and long noncoding RNA expression in T-acute lymphoblastic leukemia for clinical insights

Decoding the genetic symphony: Profiling protein-coding and long noncoding RNA expression in T-acute lymphoblastic leukemia for clinical insights

The MexTAg collaborative cross: host genetics affects asbestos related disease latency, but has little influence once tumours develop

Sustained long-term remission with tyrosine kinase inhibitor therapy in treatment-refractory B-cell acute lymphoblastic leukemia harboring a RCSD1::ABL2 fusion gene

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