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DEL(17)(Q11) IS TYPICAL MARKER OF IMMATURE T-ALL OF ADULTS, WITH NF1, UTP6, AND SUZ12 HAPLOINSUFFICIENCY, GENOME INSTABILITY, AND GENE DOWNREGULATION
Author(s): ,
Valentina Bardelli
Affiliations:
Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery ,University of Perugia,Perugia,Italie;Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery ,University of Perugia,Perugia,Italien;Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery ,University of Perugia,Perugia,Italia;Hematology and Bone Marrow Transp
,
Valentina Pierini
Affiliations:
Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italie;Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italien;Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italia;Hematology and Bone Marrow Transplan
,
Silvia Arniani
Affiliations:
Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italie;Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italien;Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italia;Hematology and Bone Marrow Transplan
,
Elena Mvridou
Affiliations:
Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italie;Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italien;Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italia;Hematology and Bone Marrow Transplan
,
Caterina Matteucci
Affiliations:
Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italie;Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italien;Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italia;Hematology and Bone Marrow Transplan
,
Anair Graciela Lema Fernandez
Affiliations:
Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italie;Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italien;Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italia;Hematology and Bone Marrow Transplan
,
Martina Moretti
Affiliations:
Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italie;Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italien;Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italia;Hematology and Bone Marrow Transplan
,
Loredana Elia
Affiliations:
Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italie;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italien;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italia;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italy;Hematology, Departme
,
Fabio Giglio
Affiliations:
Hematology and Bone Marrow Transplantation Unit,IRCCS Ospedale San Raffaele,Milan,Italie;Hematology and Bone Marrow Transplantation Unit,IRCCS Ospedale San Raffaele,Milan,Italien;Hematology and Bone Marrow Transplantation Unit,IRCCS Ospedale San Raffaele,Milan,Italia;Hematology and Bone Marrow Transplantation Unit,IRCCS Ospedale San Raffaele,Milan,Italy;Hematology and Bone Marrow Transplantation U
,
Fabio Forghieri
Affiliations:
Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia ,Modena,Italie;Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia ,Modena,Italien;Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia ,Modena,Italia;Section of Hematology, Department
,
Marco Cerrano
Affiliations:
Department of Molecular Biotechnology and Health Sciences, Division of Hematology,University of Turin,Turin,Italie;Department of Molecular Biotechnology and Health Sciences, Division of Hematology,University of Turin,Turin,Italien;Department of Molecular Biotechnology and Health Sciences, Division of Hematology,University of Turin,Turin,Italia;Department of Molecular Biotechnology and Health Scien
,
Nicola Fracchiolla
Affiliations:
Hematology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan,Italie;Hematology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan,Italien;Hematology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan,Italia;Hematology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan,Italy;Hematology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policl
,
Mario Delia
Affiliations:
Hematology and Stem Cell Transplantation Unit, AOUC Policlinico of Bari,Bari,Italie;Hematology and Stem Cell Transplantation Unit, AOUC Policlinico of Bari,Bari,Italien;Hematology and Stem Cell Transplantation Unit, AOUC Policlinico of Bari,Bari,Italia;Hematology and Stem Cell Transplantation Unit, AOUC Policlinico of Bari,Bari,Italy;Hematology and Stem Cell Transplantation Unit, AOUC Policlinico
,
Simona Sica
Affiliations:
Section of Hematology, Department of Radiological and Hematological Sciences ,Catholic University of the Sacred Heart,Rome,Italie;Section of Hematology, Department of Radiological and Hematological Sciences ,Catholic University of the Sacred Heart,Rome,Italien;Section of Hematology, Department of Radiological and Hematological Sciences ,Catholic University of the Sacred Heart,Rome,Italia;Section o
,
Cristina Mecucci
Affiliations:
Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italie;Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italien;Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italia;Hematology and Bone Marrow Transplan
Roberta La Starza
Affiliations:
Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italie;Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italien;Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery,University of Perugia,Perugia,Italia;Hematology and Bone Marrow Transplan
(Abstract release date: 05/12/22) EHA Library. Bardelli V. 06/10/22; 357171; P307
Valentina Bardelli
Valentina Bardelli
Contributions
Abstract
Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P307

Type: Poster presentation

Session title: Acute lymphoblastic leukemia - Biology & Translational Research

Background

T-ALLs derive from the accumulation of multiple genetic and epigenetic events. Some deregulate T-cell transcription factors and define specific genetic subtypes, while the large majority are involved in pivotal cellular processes, such as signaling, cell cycle, apoptosis, proliferation, ribosome biogenesis, and epigenetic modulation. Genomic imbalances, and in particular deletions, are the most frequent cytogenetic rearrangements in T-ALL. Whether cryptic or large, they often share loss regions - the common deletion region (CDR) - where they map putative suppressor genes that undergo haploinsufficiency or inactivation, thus driving the leukemogenic process.

Aims

Our study focused on T-ALL cases harboring interstitial del (17q) with the aim of assessing the incidence and distribution of this cytogenetic marker, and to detect associated clinical and molecular features.

Methods
The study was carried out on 378 adult (=223) and pediatric (=155) T-ALL, including 279 males and 99 females. The genetic background was investigated by integrated molecular-cytogenetics (FISH and SNPa),1 RNA microarrays (Affymetrix), targeted sequencing (custom card by Sophia Genetics, Arrow Diagnostics), and RTq-PCR. Data analysis was carried out referring to available databases (UCSC, NCBI, Data of Genomic Variants, Biocarta, KEGG, Reactome).

Results

Cases were classified according to genetic rearrangements as HOXA (=104), TAL/LMO (=74), TLX1/NKX2.1 (=50), TLX3 (=42), BCL11B-a (=8), SPI.1 (=2); 98 were undetermined. Interstitial monoallelic del(17q) was detected 31/378 cases and was mainly found in cases with HOXA related abnormalities (8/104) or cases undetermined (17/98). There were 27 adults and 4 children (p<0.0001). In 19/24 with available flow cytometry the diagnosis was consistent with ETP/near ETP ALL (p<0.001).

All cases shared a common deleted region (CDR) of about 650kb, that invariably involved SUZ12, UTP6, and NF1 which were expressed at a significantly lower level than in T-ALL without del(17q). RNA microarray showed that 148 differentially expressed genes (DEG), 67 up- and 81 down- regulated, distinguished del(17q) T-ALL cases from T-ALL without. Among up-regulated there were MEF2C, MN1, and IGFBP7, which have been all associated with an immature phenotype, and MAF and RUNX2 transcription factors. Instead, among down-regulated, there were putative suppressors involved in genome stability, i.e. BRCA1, FANCI, BRIP1, XRCC2, and CHEK1. Accordingly, cell cycle, homologous recombination, DNA replication, and Fanconi anemia pathways, were significantly deregulated in T-ALL with del(17q), and a significant association with deletions of RB1 (37%)(p<0.001) and TP53 (20%)(p=0.017) emerged. In addition, del(17q) cases had a higher number (≥5) of copy number abnormalities (p<0.001). Other recurrent alterations affected JAK/STAT members and/or modulators (56% of cases).

Conclusion

Del(17q) was a recurrent marker in immature T-ALL of adults and characterized 19% of cases undetermined at molecular-cytogenetic level. It caused the monoallelic loss/haploinsufficiency of three genes, i.e. NF1, UTP6, and SUZ12, that restricted the CDR. Our study provided evidence that del(17q) identified a major leukemogenic mechanism, through the cooperation of: 17q genes loss of function, JAK/STAT constitutive activation, and altered cell cycle. Interestingly, RUNX2 and IGFBP7, high-risk markers in T-ALL,2,3 were aberrantly expressed in this subset of T-ALL.

 

1La Starza R, et al. J Mol Diagn 2020

2Matthijssens F, et al. JCI 2021

3Bartram I, et. al., BMC Cancer 2015

Keyword(s): Cell cycle, Chromosomal abnormality, T-ALL

Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P307

Type: Poster presentation

Session title: Acute lymphoblastic leukemia - Biology & Translational Research

Background

T-ALLs derive from the accumulation of multiple genetic and epigenetic events. Some deregulate T-cell transcription factors and define specific genetic subtypes, while the large majority are involved in pivotal cellular processes, such as signaling, cell cycle, apoptosis, proliferation, ribosome biogenesis, and epigenetic modulation. Genomic imbalances, and in particular deletions, are the most frequent cytogenetic rearrangements in T-ALL. Whether cryptic or large, they often share loss regions - the common deletion region (CDR) - where they map putative suppressor genes that undergo haploinsufficiency or inactivation, thus driving the leukemogenic process.

Aims

Our study focused on T-ALL cases harboring interstitial del (17q) with the aim of assessing the incidence and distribution of this cytogenetic marker, and to detect associated clinical and molecular features.

Methods
The study was carried out on 378 adult (=223) and pediatric (=155) T-ALL, including 279 males and 99 females. The genetic background was investigated by integrated molecular-cytogenetics (FISH and SNPa),1 RNA microarrays (Affymetrix), targeted sequencing (custom card by Sophia Genetics, Arrow Diagnostics), and RTq-PCR. Data analysis was carried out referring to available databases (UCSC, NCBI, Data of Genomic Variants, Biocarta, KEGG, Reactome).

Results

Cases were classified according to genetic rearrangements as HOXA (=104), TAL/LMO (=74), TLX1/NKX2.1 (=50), TLX3 (=42), BCL11B-a (=8), SPI.1 (=2); 98 were undetermined. Interstitial monoallelic del(17q) was detected 31/378 cases and was mainly found in cases with HOXA related abnormalities (8/104) or cases undetermined (17/98). There were 27 adults and 4 children (p<0.0001). In 19/24 with available flow cytometry the diagnosis was consistent with ETP/near ETP ALL (p<0.001).

All cases shared a common deleted region (CDR) of about 650kb, that invariably involved SUZ12, UTP6, and NF1 which were expressed at a significantly lower level than in T-ALL without del(17q). RNA microarray showed that 148 differentially expressed genes (DEG), 67 up- and 81 down- regulated, distinguished del(17q) T-ALL cases from T-ALL without. Among up-regulated there were MEF2C, MN1, and IGFBP7, which have been all associated with an immature phenotype, and MAF and RUNX2 transcription factors. Instead, among down-regulated, there were putative suppressors involved in genome stability, i.e. BRCA1, FANCI, BRIP1, XRCC2, and CHEK1. Accordingly, cell cycle, homologous recombination, DNA replication, and Fanconi anemia pathways, were significantly deregulated in T-ALL with del(17q), and a significant association with deletions of RB1 (37%)(p<0.001) and TP53 (20%)(p=0.017) emerged. In addition, del(17q) cases had a higher number (≥5) of copy number abnormalities (p<0.001). Other recurrent alterations affected JAK/STAT members and/or modulators (56% of cases).

Conclusion

Del(17q) was a recurrent marker in immature T-ALL of adults and characterized 19% of cases undetermined at molecular-cytogenetic level. It caused the monoallelic loss/haploinsufficiency of three genes, i.e. NF1, UTP6, and SUZ12, that restricted the CDR. Our study provided evidence that del(17q) identified a major leukemogenic mechanism, through the cooperation of: 17q genes loss of function, JAK/STAT constitutive activation, and altered cell cycle. Interestingly, RUNX2 and IGFBP7, high-risk markers in T-ALL,2,3 were aberrantly expressed in this subset of T-ALL.

 

1La Starza R, et al. J Mol Diagn 2020

2Matthijssens F, et al. JCI 2021

3Bartram I, et. al., BMC Cancer 2015

Keyword(s): Cell cycle, Chromosomal abnormality, T-ALL

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