Repurposing the Whole Expression Transcriptome Assay for the Genetic Diagnosis of T-Cell Acute Lymphoblastic Leukemia and Lymphoma
Unlike other cases of acute leukemia, the diagnosis of T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is uniquely based on morphology and flow cytometry. Although the genomic background has been broadly uncovered, the large spectrum of genes involved and the variability of the molecular me...
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| Published in: | The Journal of molecular diagnostics : JMD Vol. 27; no. 5; p. 360 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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01.05.2025
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| ISSN: | 1943-7811, 1943-7811 |
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| Abstract | Unlike other cases of acute leukemia, the diagnosis of T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is uniquely based on morphology and flow cytometry. Although the genomic background has been broadly uncovered, the large spectrum of genes involved and the variability of the molecular mechanisms underlying gene deregulation have delayed the introduction of molecular cytogenetics into diagnostic flowcharts. To overcome these limitations and implement a genetic diagnosis of T-ALL/LBLs, a whole transcriptome expression assay (WTEa) was repurposed as a "priority test" to classify T-ALL/LBLs into the major genetic subtypes. A WTEa classifier based on a set of 312 probes on 215 T-ALL/LBLs was set up and applied, which properly assigned >95% of cases with subtype-defining alterations to the corresponding subgroups (ie, TAL/LMO, HOXA, TLX1, TLX3, BCL11B). It pinpointed cases that harbored cryptic alterations, such as noncoding mutations that generate new enhancer at TAL1 and LMO2 loci (8% of TAL/LMO), and duplications of noncoding element downstream BCL11B (BETA) (18% of BCL11B). It was also suitable to classify lymphoma cases for which only formalin-fixed embedded tissues were available, as confirmed in cases harboring TLX1 or TLX3 rearrangements, and distinguished new putative subtypes. WTEa offers a unifying tool to provide a genetic classification of T-ALL/LBLs. If introduced in multicenter prospective studies, it will facilitate evaluation of the clinical impact of genetic classification. |
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| AbstractList | Unlike other cases of acute leukemia, the diagnosis of T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is uniquely based on morphology and flow cytometry. Although the genomic background has been broadly uncovered, the large spectrum of genes involved and the variability of the molecular mechanisms underlying gene deregulation have delayed the introduction of molecular cytogenetics into diagnostic flowcharts. To overcome these limitations and implement a genetic diagnosis of T-ALL/LBLs, a whole transcriptome expression assay (WTEa) was repurposed as a "priority test" to classify T-ALL/LBLs into the major genetic subtypes. A WTEa classifier based on a set of 312 probes on 215 T-ALL/LBLs was set up and applied, which properly assigned >95% of cases with subtype-defining alterations to the corresponding subgroups (ie, TAL/LMO, HOXA, TLX1, TLX3, BCL11B). It pinpointed cases that harbored cryptic alterations, such as noncoding mutations that generate new enhancer at TAL1 and LMO2 loci (8% of TAL/LMO), and duplications of noncoding element downstream BCL11B (BETA) (18% of BCL11B). It was also suitable to classify lymphoma cases for which only formalin-fixed embedded tissues were available, as confirmed in cases harboring TLX1 or TLX3 rearrangements, and distinguished new putative subtypes. WTEa offers a unifying tool to provide a genetic classification of T-ALL/LBLs. If introduced in multicenter prospective studies, it will facilitate evaluation of the clinical impact of genetic classification.Unlike other cases of acute leukemia, the diagnosis of T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is uniquely based on morphology and flow cytometry. Although the genomic background has been broadly uncovered, the large spectrum of genes involved and the variability of the molecular mechanisms underlying gene deregulation have delayed the introduction of molecular cytogenetics into diagnostic flowcharts. To overcome these limitations and implement a genetic diagnosis of T-ALL/LBLs, a whole transcriptome expression assay (WTEa) was repurposed as a "priority test" to classify T-ALL/LBLs into the major genetic subtypes. A WTEa classifier based on a set of 312 probes on 215 T-ALL/LBLs was set up and applied, which properly assigned >95% of cases with subtype-defining alterations to the corresponding subgroups (ie, TAL/LMO, HOXA, TLX1, TLX3, BCL11B). It pinpointed cases that harbored cryptic alterations, such as noncoding mutations that generate new enhancer at TAL1 and LMO2 loci (8% of TAL/LMO), and duplications of noncoding element downstream BCL11B (BETA) (18% of BCL11B). It was also suitable to classify lymphoma cases for which only formalin-fixed embedded tissues were available, as confirmed in cases harboring TLX1 or TLX3 rearrangements, and distinguished new putative subtypes. WTEa offers a unifying tool to provide a genetic classification of T-ALL/LBLs. If introduced in multicenter prospective studies, it will facilitate evaluation of the clinical impact of genetic classification. Unlike other cases of acute leukemia, the diagnosis of T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is uniquely based on morphology and flow cytometry. Although the genomic background has been broadly uncovered, the large spectrum of genes involved and the variability of the molecular mechanisms underlying gene deregulation have delayed the introduction of molecular cytogenetics into diagnostic flowcharts. To overcome these limitations and implement a genetic diagnosis of T-ALL/LBLs, a whole transcriptome expression assay (WTEa) was repurposed as a "priority test" to classify T-ALL/LBLs into the major genetic subtypes. A WTEa classifier based on a set of 312 probes on 215 T-ALL/LBLs was set up and applied, which properly assigned >95% of cases with subtype-defining alterations to the corresponding subgroups (ie, TAL/LMO, HOXA, TLX1, TLX3, BCL11B). It pinpointed cases that harbored cryptic alterations, such as noncoding mutations that generate new enhancer at TAL1 and LMO2 loci (8% of TAL/LMO), and duplications of noncoding element downstream BCL11B (BETA) (18% of BCL11B). It was also suitable to classify lymphoma cases for which only formalin-fixed embedded tissues were available, as confirmed in cases harboring TLX1 or TLX3 rearrangements, and distinguished new putative subtypes. WTEa offers a unifying tool to provide a genetic classification of T-ALL/LBLs. If introduced in multicenter prospective studies, it will facilitate evaluation of the clinical impact of genetic classification. |
| Author | Nardelli, Carlotta Zappasodi, Patrizia Montefiori, Lindsey E Sica, Simona La Starza, Roberta Trappolini, Silvia Defina, Marzia Di Giacomo, Danika Lema Fernandez, Anair Graciela Mastaglio, Sara Bardelli, Valentina Crocioni, Maria Pierini, Valentina Cerrano, Marco Giglio, Fabio Matteucci, Caterina Pasciolla, Crescenza Lanzarone, Giuseppe Mecucci, Cristina Salutari, Prassede Papayanidis, Cristina Arniani, Silvia Piccini, Matteo Mullighan, Charles G |
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Città della Salute e della Scienza, Turin, Italy – sequence: 9 givenname: Prassede surname: Salutari fullname: Salutari, Prassede organization: Hematology Unit, Ospedale Civile Santo Spirito, Pescara, Italy – sequence: 10 givenname: Cristina surname: Papayanidis fullname: Papayanidis, Cristina organization: IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "L. & A. Seràgnoli," Bologna, Italy – sequence: 11 givenname: Silvia surname: Trappolini fullname: Trappolini, Silvia organization: Hematology Clinic, AOU Marche, Ancona, Italy – sequence: 12 givenname: Fabio surname: Giglio fullname: Giglio, Fabio organization: OncoHematology Division, European Institute of Oncology, Milan, Italy – sequence: 13 givenname: Sara surname: Mastaglio fullname: Mastaglio, Sara organization: Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital, Milan, Italy – sequence: 14 givenname: Patrizia surname: Zappasodi fullname: Zappasodi, Patrizia organization: Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy – sequence: 15 givenname: Crescenza surname: Pasciolla fullname: Pasciolla, Crescenza organization: Hematology Unit, IRCCS Istituto Tumori "Giovanni Paolo II," Bari, Italy – sequence: 16 givenname: Marzia surname: Defina fullname: Defina, Marzia organization: Hematology Unit, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena, Italy – sequence: 17 givenname: Matteo surname: Piccini fullname: Piccini, Matteo organization: Hematology Department, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy – sequence: 18 givenname: Giuseppe surname: Lanzarone fullname: Lanzarone, Giuseppe organization: Department of Molecular Biotechnology and Health Sciences, Division of Hematology, University of Torino, Turin, Italy – sequence: 19 givenname: Danika surname: Di Giacomo fullname: Di Giacomo, Danika organization: Hematology and Bone Marrow Transplantation Section, Department of Medicine and Surgery, University of Perugia, Centro di Ricerche EmatoOncologiche, Azienda di Perugia (CREO A.O.), Perugia, Italy; Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy – sequence: 20 givenname: Simona surname: Sica fullname: Sica, Simona organization: Haematology Unit, Department of Radiological and Hematological Sciences, Università Cattolica del Sacro Cuore, Rome, Italy – sequence: 21 givenname: Lindsey E surname: Montefiori fullname: Montefiori, Lindsey E organization: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee – sequence: 22 givenname: Charles G surname: Mullighan fullname: Mullighan, Charles G organization: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee – sequence: 23 givenname: Cristina surname: Mecucci fullname: Mecucci, Cristina organization: Hematology and Bone Marrow Transplantation Section, Department of Medicine and Surgery, University of Perugia, Centro di Ricerche EmatoOncologiche, Azienda di Perugia (CREO A.O.), Perugia, Italy – sequence: 24 givenname: Roberta surname: La Starza fullname: La Starza, Roberta email: roberta.lastarza@unipg.it organization: Hematology and Bone Marrow Transplantation Section, Department of Medicine and Surgery, University of Perugia, Centro di Ricerche EmatoOncologiche, Azienda di Perugia (CREO A.O.), Perugia, Italy. Electronic address: roberta.lastarza@unipg.it |
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| SubjectTerms | Gene Expression Profiling - methods Humans Mutation Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - diagnosis Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics Transcriptome |
| Title | Repurposing the Whole Expression Transcriptome Assay for the Genetic Diagnosis of T-Cell Acute Lymphoblastic Leukemia and Lymphoma |
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