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UBTF-ATXN7L3 GENE FUSION DUE TO 17Q21.31 DELETION DEFINES NOVEL HIGH-RISK ALL SUBTYPE AMENABLE TO MRD-BASED TREATMENT INTENSIFICATION
Author(s): ,
Lorenz Bastian
Affiliations:
Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Allemagne;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Deutschland;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Germania;Department of Medicine II, Hematology and Oncolo
,
Alina Hartmann
Affiliations:
Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Allemagne;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Deutschland;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Germania;Department of Medicine II, Hematology and Oncolo
,
Thomas Beder
Affiliations:
Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Allemagne;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Deutschland;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Germania;Department of Medicine II, Hematology and Oncolo
,
Sonja Hänzelmann
Affiliations:
Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Allemagne;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Deutschland;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Germania;Department of Medicine II, Hematology and Oncolo
,
Jan Kässens
Affiliations:
Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Allemagne;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Deutschland;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Germania;Department of Medicine II, Hematology and Oncolo
,
Miriam Bultmann
Affiliations:
Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Allemagne;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Deutschland;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Germania;Department of Medicine II, Hematology and Oncolo
,
Marc P. Höppner
Affiliations:
Institute for Clinical Molecular Biology,Kiel University,Kiel,Allemagne;Institute for Clinical Molecular Biology,Kiel University,Kiel,Deutschland;Institute for Clinical Molecular Biology,Kiel University,Kiel,Germania;Institute for Clinical Molecular Biology,Kiel University,Kiel,Germany;Institute for Clinical Molecular Biology,Kiel University,Kiel,Alemania;Institute for Clinical Molecular Biology,K
,
Sören Franzenburg
Affiliations:
Institute for Clinical Molecular Biology,Kiel University,Kiel,Allemagne;Institute for Clinical Molecular Biology,Kiel University,Kiel,Deutschland;Institute for Clinical Molecular Biology,Kiel University,Kiel,Germania;Institute for Clinical Molecular Biology,Kiel University,Kiel,Germany;Institute for Clinical Molecular Biology,Kiel University,Kiel,Alemania;Institute for Clinical Molecular Biology,K
,
Michael Wittig
Affiliations:
Institute for Clinical Molecular Biology,Kiel University,Kiel,Allemagne;Institute for Clinical Molecular Biology,Kiel University,Kiel,Deutschland;Institute for Clinical Molecular Biology,Kiel University,Kiel,Germania;Institute for Clinical Molecular Biology,Kiel University,Kiel,Germany;Institute for Clinical Molecular Biology,Kiel University,Kiel,Alemania;Institute for Clinical Molecular Biology,K
,
Andre Franke
Affiliations:
Institute for Clinical Molecular Biology,Kiel University,Kiel,Allemagne;Institute for Clinical Molecular Biology,Kiel University,Kiel,Deutschland;Institute for Clinical Molecular Biology,Kiel University,Kiel,Germania;Institute for Clinical Molecular Biology,Kiel University,Kiel,Germany;Institute for Clinical Molecular Biology,Kiel University,Kiel,Alemania;Institute for Clinical Molecular Biology,K
,
Inga Nagel
Affiliations:
Institute of Human Genetics,University Medical Center Schleswig-Holstein, Kiel and Lübeck,Kiel and Lübeck,Allemagne;Institute of Human Genetics,University Medical Center Schleswig-Holstein, Kiel and Lübeck,Kiel and Lübeck,Deutschland;Institute of Human Genetics,University Medical Center Schleswig-Holstein, Kiel and Lübeck,Kiel and Lübeck,Germania;Institute of Human Genetics,University Medical Cent
,
Malte Spielmann
Affiliations:
Institute of Human Genetics,University Medical Center Schleswig-Holstein, Kiel and Lübeck,Kiel and Lübeck,Allemagne;Institute of Human Genetics,University Medical Center Schleswig-Holstein, Kiel and Lübeck,Kiel and Lübeck,Deutschland;Institute of Human Genetics,University Medical Center Schleswig-Holstein, Kiel and Lübeck,Kiel and Lübeck,Germania;Institute of Human Genetics,University Medical Cent
,
Niklas Reimer
Affiliations:
Medical Systems Biology Group and Institute for Cardiogenetics,University of Lübeck,Lübeck,Allemagne;Medical Systems Biology Group and Institute for Cardiogenetics,University of Lübeck,Lübeck,Deutschland;Medical Systems Biology Group and Institute for Cardiogenetics,University of Lübeck,Lübeck,Germania;Medical Systems Biology Group and Institute for Cardiogenetics,University of Lübeck,Lübeck,Germa
,
Hauke Busch
Affiliations:
Medical Systems Biology Group and Institute for Cardiogenetics,University of Lübeck,Lübeck,Allemagne;Medical Systems Biology Group and Institute for Cardiogenetics,University of Lübeck,Lübeck,Deutschland;Medical Systems Biology Group and Institute for Cardiogenetics,University of Lübeck,Lübeck,Germania;Medical Systems Biology Group and Institute for Cardiogenetics,University of Lübeck,Lübeck,Germa
,
Stefan Schwartz
Affiliations:
Department of Hematology, Oncology and Tumor Immunology (Campus Benjamin Franklin),Charité - Universitätsmedizin Berlin,Berlin,Allemagne;Department of Hematology, Oncology and Tumor Immunology (Campus Benjamin Franklin),Charité - Universitätsmedizin Berlin,Berlin,Deutschland;Department of Hematology, Oncology and Tumor Immunology (Campus Benjamin Franklin),Charité - Universitätsmedizin Berlin,Berl
,
Björn Steffen
Affiliations:
Department of Medicine II, Hematology/Oncology,Goethe University Hospital,Frankfurt / Main,Allemagne;Department of Medicine II, Hematology/Oncology,Goethe University Hospital,Frankfurt / Main,Deutschland;Department of Medicine II, Hematology/Oncology,Goethe University Hospital,Frankfurt / Main,Germania;Department of Medicine II, Hematology/Oncology,Goethe University Hospital,Frankfurt / Main,Germa
,
Andreas Viardot
Affiliations:
Department of Internal Medicine III,University Hospital Ulm,Ulm,Allemagne;Department of Internal Medicine III,University Hospital Ulm,Ulm,Deutschland;Department of Internal Medicine III,University Hospital Ulm,Ulm,Germania;Department of Internal Medicine III,University Hospital Ulm,Ulm,Germany;Department of Internal Medicine III,University Hospital Ulm,Ulm,Alemania;Department of Internal Medicine
,
Konstanze Döhner
Affiliations:
Department of Internal Medicine III,University Hospital Ulm,Ulm,Allemagne;Department of Internal Medicine III,University Hospital Ulm,Ulm,Deutschland;Department of Internal Medicine III,University Hospital Ulm,Ulm,Germania;Department of Internal Medicine III,University Hospital Ulm,Ulm,Germany;Department of Internal Medicine III,University Hospital Ulm,Ulm,Alemania;Department of Internal Medicine
,
Mustafa Kondakci
Affiliations:
Department of Hematology, Oncology and Clinical Immunology,University Hospital Düsseldorf,Düsseldorf,Allemagne;Department of Hematology, Oncology and Clinical Immunology,University Hospital Düsseldorf,Düsseldorf,Deutschland;Department of Hematology, Oncology and Clinical Immunology,University Hospital Düsseldorf,Düsseldorf,Germania;Department of Hematology, Oncology and Clinical Immunology,Univers
,
Gerald Wulf
Affiliations:
Department of Hematology and Oncology,University Hospital Göttingen,Göttingen,Allemagne;Department of Hematology and Oncology,University Hospital Göttingen,Göttingen,Deutschland;Department of Hematology and Oncology,University Hospital Göttingen,Göttingen,Germania;Department of Hematology and Oncology,University Hospital Göttingen,Göttingen,Germany;Department of Hematology and Oncology,University
,
Knut Wendelin
Affiliations:
Medical Department V,Hospital Nürnberg, Paracelsus Medizinische Privatuniversität,Nürnberg,Allemagne;Medical Department V,Hospital Nürnberg, Paracelsus Medizinische Privatuniversität,Nürnberg,Deutschland;Medical Department V,Hospital Nürnberg, Paracelsus Medizinische Privatuniversität,Nürnberg,Germania;Medical Department V,Hospital Nürnberg, Paracelsus Medizinische Privatuniversität,Nürnberg,Germa
,
Andrea Renzelmann
Affiliations:
Medical Department Oncology and Hematology,University Medical Center Oldenburg,Oldenburg,Allemagne;Medical Department Oncology and Hematology,University Medical Center Oldenburg,Oldenburg,Deutschland;Medical Department Oncology and Hematology,University Medical Center Oldenburg,Oldenburg,Germania;Medical Department Oncology and Hematology,University Medical Center Oldenburg,Oldenburg,Germany;Medic
,
Alexander Kiani
Affiliations:
Department of Medicine IV, Hematology/Oncology,Klinikum Bayreuth,Bayreuth,Allemagne;Department of Medicine IV, Hematology/Oncology,Klinikum Bayreuth,Bayreuth,Deutschland;Department of Medicine IV, Hematology/Oncology,Klinikum Bayreuth,Bayreuth,Germania;Department of Medicine IV, Hematology/Oncology,Klinikum Bayreuth,Bayreuth,Germany;Department of Medicine IV, Hematology/Oncology,Klinikum Bayreuth,
,
Heiko Trautmann
Affiliations:
Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Allemagne;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Deutschland;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Germania;Department of Medicine II, Hematology and Oncolo
,
Martin Neumann
Affiliations:
Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Allemagne;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Deutschland;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Germania;Department of Medicine II, Hematology and Oncolo
,
Nicola Gökbuget
Affiliations:
Department of Medicine II, Hematology/Oncology,Goethe University Hospital,Frankfurt / Main,Allemagne;Department of Medicine II, Hematology/Oncology,Goethe University Hospital,Frankfurt / Main,Deutschland;Department of Medicine II, Hematology/Oncology,Goethe University Hospital,Frankfurt / Main,Germania;Department of Medicine II, Hematology/Oncology,Goethe University Hospital,Frankfurt / Main,Germa
,
Monika Brüggemann
Affiliations:
Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Allemagne;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Deutschland;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Germania;Department of Medicine II, Hematology and Oncolo
Claudia Baldus
Affiliations:
Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Allemagne;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Deutschland;Department of Medicine II, Hematology and Oncology,University Medical Center Schleswig-Holstein, Kiel,Kiel,Germania;Department of Medicine II, Hematology and Oncolo
(Abstract release date: 05/12/22) EHA Library. Bastian L. 06/11/22; 356971; S106
Lorenz Bastian
Lorenz Bastian
Contributions
Abstract
Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S106

Type: Oral Presentation

Session title: From biology to preclinical models in ALL

Background

Response to induction chemotherapy assessed by quantification of minimal residual disease (MRD) is the strongest independent prognosticator in B precursor acute lymphoblastic leukemia (BCP-ALL). Molecular underpinnings of MRD poor response are insufficiently understood.

Aims

We aimed to identify novel high-risk subtypes in adult BCP-ALL as cell-intrinsic determinants of MRD poor response.

Methods

Adult BCP-ALL patients (n=565) were treated according to pediatric inspired protocols of the German Acute Lymphoblastic Leukemia Study group (GMALL) and profiled for integrative analyses by RNA-Seq (n=565), SNP-arrays (n=115), whole exome sequencing (WES; n=84) and whole genome sequencing (WGS; n=3).

Results

Concordance between transcriptomic and genomic profiles was used to allocate samples to one of 15 established molecular driver subgroups (Figure A). Unsupervised clustering of gene expression from the remaining samples revealed a distinct cluster (n=12/565, 2.1%) with an in-frame gene fusion between upstream binding transcription factor (UBTF) and ataxin-7-like protein 3 (ATXN7L3) as exclusive event in these patients. Both fusion partners are in direct neighborship at 17q21.31. WGS revealed a 10.08 kb genomic deletion which truncated UBTF at exon 17/21 and comprised most of the intergenic region between both genes (Figure B). UBTF-ATXN7L3 rearranged cases frequently harbored 1q gains (n=5/7). Further genomic profiling showed a remarkable paucity of additional cooperating events compared to other molecular subtypes, supporting a prominent driver function of the newly identified fusion. UBTF and ATXN7L3 are global epigenetic regulators involved in transcriptional control. Both genes were highly expressed across the entire cohort. The gene fusion was associated with a marked increase of Caudal Homeobox 2 (CDX2) expression. Analysis of functional modules related CDX2 to upregulated HOXA9 and MEIS1, described essential co-regulators of KMT2A-driven leukemogenesis. NTRK3 expression was also strongly upregulated, suggesting a possible rationale for specific inhibitors.

UBTF-AXTN7L3 rearranged patients were older, more frequently female and presented with normal leukocyte counts, low bone marrow infiltration and pro-B immunophenotypes or common ALL with reduced CD10 expression. Response to induction chemotherapy in evaluable patients (n=11) was poor with only 3 patients achieving MRD negativity after consolidation I compared to n=271/402 (67%; p=0.019) in the remaining cohort. Four patients suffered either cytologic (n=2) or molecular (n=2) relapse. Immunotherapeutic treatment intensification using blinatumomab (n=5) or inotuzumab ozogamizin (n=1) and / or allogenic stem cell transplantation (n=7) in MRD poor responders or relapsed cases resulted in an overall survival probability of 80% (+/- 12%) vs. 73% (+/- 2%; p=0.07) in the remaining cohort. Heterogeneous MRD responses were observed for other molecular subtypes (poor: ZNF384 - 48.2% MRD neg., p=0.056; Ph-like - 54.0% MRD neg., p=0.003; KMT2A - 55.8% MRD neg., p=0.127 / good: High Hyperdiploid - 90.9% MRD neg., p=0.01; TCF3-PBX1 - 94.1% MRD neg., p=0.016) indicating how molecular drivers affect chemo-sensitivity in adult BCP-ALL.

Conclusion

Molecular driver alterations determine sensitivity to induction chemotherapy in adult BCP-ALL. UBTF-ATXN7L3 ALL represents a novel subtype with poor induction chemotherapy response which could be successfully salvaged by MRD-based treatment intensification using immunotherapeutic strategies.

Keyword(s): Acute lymphoblastic leukemia, Leukemogenesis, Minimal residual disease (MRD), Molecular cytogenetics

Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S106

Type: Oral Presentation

Session title: From biology to preclinical models in ALL

Background

Response to induction chemotherapy assessed by quantification of minimal residual disease (MRD) is the strongest independent prognosticator in B precursor acute lymphoblastic leukemia (BCP-ALL). Molecular underpinnings of MRD poor response are insufficiently understood.

Aims

We aimed to identify novel high-risk subtypes in adult BCP-ALL as cell-intrinsic determinants of MRD poor response.

Methods

Adult BCP-ALL patients (n=565) were treated according to pediatric inspired protocols of the German Acute Lymphoblastic Leukemia Study group (GMALL) and profiled for integrative analyses by RNA-Seq (n=565), SNP-arrays (n=115), whole exome sequencing (WES; n=84) and whole genome sequencing (WGS; n=3).

Results

Concordance between transcriptomic and genomic profiles was used to allocate samples to one of 15 established molecular driver subgroups (Figure A). Unsupervised clustering of gene expression from the remaining samples revealed a distinct cluster (n=12/565, 2.1%) with an in-frame gene fusion between upstream binding transcription factor (UBTF) and ataxin-7-like protein 3 (ATXN7L3) as exclusive event in these patients. Both fusion partners are in direct neighborship at 17q21.31. WGS revealed a 10.08 kb genomic deletion which truncated UBTF at exon 17/21 and comprised most of the intergenic region between both genes (Figure B). UBTF-ATXN7L3 rearranged cases frequently harbored 1q gains (n=5/7). Further genomic profiling showed a remarkable paucity of additional cooperating events compared to other molecular subtypes, supporting a prominent driver function of the newly identified fusion. UBTF and ATXN7L3 are global epigenetic regulators involved in transcriptional control. Both genes were highly expressed across the entire cohort. The gene fusion was associated with a marked increase of Caudal Homeobox 2 (CDX2) expression. Analysis of functional modules related CDX2 to upregulated HOXA9 and MEIS1, described essential co-regulators of KMT2A-driven leukemogenesis. NTRK3 expression was also strongly upregulated, suggesting a possible rationale for specific inhibitors.

UBTF-AXTN7L3 rearranged patients were older, more frequently female and presented with normal leukocyte counts, low bone marrow infiltration and pro-B immunophenotypes or common ALL with reduced CD10 expression. Response to induction chemotherapy in evaluable patients (n=11) was poor with only 3 patients achieving MRD negativity after consolidation I compared to n=271/402 (67%; p=0.019) in the remaining cohort. Four patients suffered either cytologic (n=2) or molecular (n=2) relapse. Immunotherapeutic treatment intensification using blinatumomab (n=5) or inotuzumab ozogamizin (n=1) and / or allogenic stem cell transplantation (n=7) in MRD poor responders or relapsed cases resulted in an overall survival probability of 80% (+/- 12%) vs. 73% (+/- 2%; p=0.07) in the remaining cohort. Heterogeneous MRD responses were observed for other molecular subtypes (poor: ZNF384 - 48.2% MRD neg., p=0.056; Ph-like - 54.0% MRD neg., p=0.003; KMT2A - 55.8% MRD neg., p=0.127 / good: High Hyperdiploid - 90.9% MRD neg., p=0.01; TCF3-PBX1 - 94.1% MRD neg., p=0.016) indicating how molecular drivers affect chemo-sensitivity in adult BCP-ALL.

Conclusion

Molecular driver alterations determine sensitivity to induction chemotherapy in adult BCP-ALL. UBTF-ATXN7L3 ALL represents a novel subtype with poor induction chemotherapy response which could be successfully salvaged by MRD-based treatment intensification using immunotherapeutic strategies.

Keyword(s): Acute lymphoblastic leukemia, Leukemogenesis, Minimal residual disease (MRD), Molecular cytogenetics

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