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PEDIATRIC T- ALL RELAPSE: CONSTITUTIONAL CANCER PREDISPOSITION AND HYPERMUTATATOR PHENOTYPES
Author(s): ,
Paulina Richter-Pechanska
Affiliations:
University Hospital Heidelberg,Heidelberg,Allemagne;University Hospital Heidelberg,Heidelberg,Deutschland;University Hospital Heidelberg,Heidelberg,Germania;University Hospital Heidelberg,Heidelberg,Germany;University Hospital Heidelberg,Heidelberg,Alemania;University Hospital Heidelberg,Heidelberg,Duitsland;University Hospital Heidelberg,Heidelberg,Alemanha;University Hospital Heidelberg,Heidelbe
,
Joachim Kunz
Affiliations:
University Hospital Heidelberg,Heidelberg,Allemagne;University Hospital Heidelberg,Heidelberg,Deutschland;University Hospital Heidelberg,Heidelberg,Germania;University Hospital Heidelberg,Heidelberg,Germany;University Hospital Heidelberg,Heidelberg,Alemania;University Hospital Heidelberg,Heidelberg,Duitsland;University Hospital Heidelberg,Heidelberg,Alemanha;University Hospital Heidelberg,Heidelbe
,
Tobias Rausch
Affiliations:
EMBL,Heidelberg,Allemagne;EMBL,Heidelberg,Deutschland;EMBL,Heidelberg,Germania;EMBL,Heidelberg,Germany;EMBL,Heidelberg,Alemania;EMBL,Heidelberg,Duitsland;EMBL,Heidelberg,Alemanha;EMBL,Heidelberg,Германия;EMBL,Heidelberg,Tyskland;MMPU,Heidelberg,Allemagne;MMPU,Heidelberg,Deutschland;MMPU,Heidelberg,Germania;MMPU,Heidelberg,Germany;MMPU,Heidelberg,Alemania;MMPU,Heidelberg,Duitsland;MMPU,Heidelberg,A
,
Busra Erarslan-Uysal
Affiliations:
University Hospital Heidelberg,Heidelberg,Allemagne;University Hospital Heidelberg,Heidelberg,Deutschland;University Hospital Heidelberg,Heidelberg,Germania;University Hospital Heidelberg,Heidelberg,Germany;University Hospital Heidelberg,Heidelberg,Alemania;University Hospital Heidelberg,Heidelberg,Duitsland;University Hospital Heidelberg,Heidelberg,Alemanha;University Hospital Heidelberg,Heidelbe
,
Beat Bornhauser
Affiliations:
University Children's Hospital,Zürich,Suisse;University Children's Hospital,Zürich,Schweiz;University Children's Hospital,Zürich,Svizzera;University Children's Hospital,Zürich,Switzerland;University Children's Hospital,Zürich,Suiza;University Children's Hospital,Zürich,Zwitserland;University Children's Hospital,Zürich,Suíça;University Children's Hospital,Zürich,Швейцария ;University Children's Hos
,
Viktoras Frismantas
Affiliations:
University Children's Hospital,Zürich,Suisse;University Children's Hospital,Zürich,Schweiz;University Children's Hospital,Zürich,Svizzera;University Children's Hospital,Zürich,Switzerland;University Children's Hospital,Zürich,Suiza;University Children's Hospital,Zürich,Zwitserland;University Children's Hospital,Zürich,Suíça;University Children's Hospital,Zürich,Швейцария ;University Children's Hos
,
Yassen Assenov
Affiliations:
DKFZ,Heidelberg,Allemagne;DKFZ,Heidelberg,Deutschland;DKFZ,Heidelberg,Germania;DKFZ,Heidelberg,Germany;DKFZ,Heidelberg,Alemania;DKFZ,Heidelberg,Duitsland;DKFZ,Heidelberg,Alemanha;DKFZ,Heidelberg,Германия;DKFZ,Heidelberg,Tyskland
,
Martin Zimmermann
Affiliations:
Hannover Medical School,Hannover,Allemagne;Hannover Medical School,Hannover,Deutschland;Hannover Medical School,Hannover,Germania;Hannover Medical School,Hannover,Germany;Hannover Medical School,Hannover,Alemania;Hannover Medical School,Hannover,Duitsland;Hannover Medical School,Hannover,Alemanha;Hannover Medical School,Hannover,Германия;Hannover Medical School,Hannover,Tyskland
,
Margit Happich
Affiliations:
University Hospital Heidelberg,Heidelberg,Allemagne;University Hospital Heidelberg,Heidelberg,Deutschland;University Hospital Heidelberg,Heidelberg,Germania;University Hospital Heidelberg,Heidelberg,Germany;University Hospital Heidelberg,Heidelberg,Alemania;University Hospital Heidelberg,Heidelberg,Duitsland;University Hospital Heidelberg,Heidelberg,Alemanha;University Hospital Heidelberg,Heidelbe
,
Caroline von Knebel-Doeberitz
Affiliations:
University Hospital Heidelberg,Heidelberg,Allemagne;University Hospital Heidelberg,Heidelberg,Deutschland;University Hospital Heidelberg,Heidelberg,Germania;University Hospital Heidelberg,Heidelberg,Germany;University Hospital Heidelberg,Heidelberg,Alemania;University Hospital Heidelberg,Heidelberg,Duitsland;University Hospital Heidelberg,Heidelberg,Alemanha;University Hospital Heidelberg,Heidelbe
,
Nils von Neuhoff
Affiliations:
University Hospital, University of Duisburg-Essen,Essen,Allemagne;University Hospital, University of Duisburg-Essen,Essen,Deutschland;University Hospital, University of Duisburg-Essen,Essen,Germania;University Hospital, University of Duisburg-Essen,Essen,Germany;University Hospital, University of Duisburg-Essen,Essen,Alemania;University Hospital, University of Duisburg-Essen,Essen,Duitsland;Univer
,
Rolf Koehler
Affiliations:
University Heidelberg,Heidelberg,Allemagne;University Heidelberg,Heidelberg,Deutschland;University Heidelberg,Heidelberg,Germania;University Heidelberg,Heidelberg,Germany;University Heidelberg,Heidelberg,Alemania;University Heidelberg,Heidelberg,Duitsland;University Heidelberg,Heidelberg,Alemanha;University Heidelberg,Heidelberg,Германия;University Heidelberg,Heidelberg,Tyskland
,
Martin Stanulla
Affiliations:
Hannover Medical School,Hannover,Allemagne;Hannover Medical School,Hannover,Deutschland;Hannover Medical School,Hannover,Germania;Hannover Medical School,Hannover,Germany;Hannover Medical School,Hannover,Alemania;Hannover Medical School,Hannover,Duitsland;Hannover Medical School,Hannover,Alemanha;Hannover Medical School,Hannover,Германия;Hannover Medical School,Hannover,Tyskland
,
Martin Schrappe
Affiliations:
University Hospital Schleswig-Holstein,Kiel,Allemagne;University Hospital Schleswig-Holstein,Kiel,Deutschland;University Hospital Schleswig-Holstein,Kiel,Germania;University Hospital Schleswig-Holstein,Kiel,Germany;University Hospital Schleswig-Holstein,Kiel,Alemania;University Hospital Schleswig-Holstein,Kiel,Duitsland;University Hospital Schleswig-Holstein,Kiel,Alemanha;University Hospital Schle
,
Gunnar Cario
Affiliations:
University Hospital Schleswig-Holstein,Kiel,Allemagne;University Hospital Schleswig-Holstein,Kiel,Deutschland;University Hospital Schleswig-Holstein,Kiel,Germania;University Hospital Schleswig-Holstein,Kiel,Germany;University Hospital Schleswig-Holstein,Kiel,Alemania;University Hospital Schleswig-Holstein,Kiel,Duitsland;University Hospital Schleswig-Holstein,Kiel,Alemanha;University Hospital Schle
,
Gabriele Escherich
Affiliations:
University Medical Center Hamburg-Eppendorf,Hamburg,Allemagne;University Medical Center Hamburg-Eppendorf,Hamburg,Deutschland;University Medical Center Hamburg-Eppendorf,Hamburg,Germania;University Medical Center Hamburg-Eppendorf,Hamburg,Germany;University Medical Center Hamburg-Eppendorf,Hamburg,Alemania;University Medical Center Hamburg-Eppendorf,Hamburg,Duitsland;University Medical Center Hamb
,
Renate Kischner-Schwabe
Affiliations:
Charite,Berlin,Allemagne;Charite,Berlin,Deutschland;Charite,Berlin,Germania;Charite,Berlin,Germany;Charite,Berlin,Alemania;Charite,Berlin,Duitsland;Charite,Berlin,Alemanha;Charite,Berlin,Германия;Charite,Berlin,Tyskland
,
Cornelia Eckert
Affiliations:
Charite,Berlin,Allemagne;Charite,Berlin,Deutschland;Charite,Berlin,Germania;Charite,Berlin,Germany;Charite,Berlin,Alemania;Charite,Berlin,Duitsland;Charite,Berlin,Alemanha;Charite,Berlin,Германия;Charite,Berlin,Tyskland
,
Smadar Avigad
Affiliations:
Schneider Children's Medical Center of Israel,Petah Tikva,Israël;Schneider Children's Medical Center of Israel,Petah Tikva,Israel;Schneider Children's Medical Center of Israel,Petah Tikva,Israele;Schneider Children's Medical Center of Israel,Petah Tikva,Israel;Schneider Children's Medical Center of Israel,Petah Tikva,Israel;Schneider Children's Medical Center of Israel,Petah Tikva,Israel;Schneider
,
Stefan Pfister
Affiliations:
DKFZ,Heidelberg,Allemagne;DKFZ,Heidelberg,Deutschland;DKFZ,Heidelberg,Germania;DKFZ,Heidelberg,Germany;DKFZ,Heidelberg,Alemania;DKFZ,Heidelberg,Duitsland;DKFZ,Heidelberg,Alemanha;DKFZ,Heidelberg,Германия;DKFZ,Heidelberg,Tyskland;KiTZ,Heidelberg,Allemagne;KiTZ,Heidelberg,Deutschland;KiTZ,Heidelberg,Germania;KiTZ,Heidelberg,Germany;KiTZ,Heidelberg,Alemania;KiTZ,Heidelberg,Duitsland;KiTZ,Heidelberg,A
,
Martina Muckenthaler
Affiliations:
University Hospital Heidelberg,Heidelberg,Allemagne;University Hospital Heidelberg,Heidelberg,Deutschland;University Hospital Heidelberg,Heidelberg,Germania;University Hospital Heidelberg,Heidelberg,Germany;University Hospital Heidelberg,Heidelberg,Alemania;University Hospital Heidelberg,Heidelberg,Duitsland;University Hospital Heidelberg,Heidelberg,Alemanha;University Hospital Heidelberg,Heidelbe
,
Jean-Pierre Bourquin
Affiliations:
University Children's Hospital,Zürich,Suisse;University Children's Hospital,Zürich,Schweiz;University Children's Hospital,Zürich,Svizzera;University Children's Hospital,Zürich,Switzerland;University Children's Hospital,Zürich,Suiza;University Children's Hospital,Zürich,Zwitserland;University Children's Hospital,Zürich,Suíça;University Children's Hospital,Zürich,Швейцария ;University Children's Hos
,
Jan Korbel
Affiliations:
EMBL,Heidelberg,Allemagne;EMBL,Heidelberg,Deutschland;EMBL,Heidelberg,Germania;EMBL,Heidelberg,Germany;EMBL,Heidelberg,Alemania;EMBL,Heidelberg,Duitsland;EMBL,Heidelberg,Alemanha;EMBL,Heidelberg,Германия;EMBL,Heidelberg,Tyskland;MMPU,Heidelberg,Allemagne;MMPU,Heidelberg,Deutschland;MMPU,Heidelberg,Germania;MMPU,Heidelberg,Germany;MMPU,Heidelberg,Alemania;MMPU,Heidelberg,Duitsland;MMPU,Heidelberg,A
Andreas Kulozik
Affiliations:
University Hospital Heidelberg,Heidelberg,Allemagne;University Hospital Heidelberg,Heidelberg,Deutschland;University Hospital Heidelberg,Heidelberg,Germania;University Hospital Heidelberg,Heidelberg,Germany;University Hospital Heidelberg,Heidelberg,Alemania;University Hospital Heidelberg,Heidelberg,Duitsland;University Hospital Heidelberg,Heidelberg,Alemanha;University Hospital Heidelberg,Heidelbe
(Abstract release date: 05/12/22) EHA Library. Richter-Pechanska P. 06/11/22; 356973; S108
Paulina Richter-Pechanska
Paulina Richter-Pechanska
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: S108

Type: Oral Presentation

Session title: From biology to preclinical models in ALL

Background
Relapse is the main cause of death from pediatric acute precursor T-cell leukemia (T-ALL), but the underlying mechanisms of disease evolution from initial disease to relapse remain incompletely understood and show remarkable interpatient heterogeneity.

Aims
As cross-sectional studies failed to identify unifying determinants of relapse, we adopted a longitudinal strategy and performed multi-omic analyses in 13 matched pairs of initial diagnosis and relapse samples and their matched PDXs. We extended this set by WES and methylome analyses in an additional cohort of 25 matched DNA samples from patient cells collected at initial diagnosis, remission, and relapse.

Methods
Thirty-eight patients were recruited from the ALL‐BFM 2000/2009, CoALL97/03/09, and ALL‐REZ BFM 2002 trials or from Schneider Children’s Medical Center of Israel at time points of initial diagnosis, remission, and relapse. Material from 13 matched pairs of PDXs (RNA, cells) was used for multi-omic analyses, including DNA-Seq (WES), RNA-Seq, ATAC-Seq and methylation analysis with EPIC arrays.

Results

Based on the profile of SNVs and InDels we distinguished 18 (47%) type-1 (derived from the major ancestral clone) and 20 (53%) type-2 relapses (derived from a minor ancestral clone). We observed stronger remodeling on the way to type 2 than to type 1 relapses reflected by more evident changes in methylation, chromatin accessibility and gene expression. At the time of relapse, 3/20 type 2 patients exhibited a hypermutator phenotype, probably caused by gains of mutations in TP53, BLM and BUB1B combined with PMS2. Moreover, type 2 T-ALLs were predominantly TAL1-driven (4/8) in contrary to type 1 (0/5). T-ALLs that later progressed to type-2 relapses exhibited a complex subclonal architecture, unexpectedly, already at the time of initial diagnosis. The fraction of subclonal mutations of those T-ALLs that later developed into a type-2 relapse was significantly higher already at the time of initial diagnosis than in those T-ALLs that later developed into a type-1 relapse (p=0.0387; Fisher’s exact), a difference that became even more pronounced at the time of relapse (p<0.0001). On the other hand, relapse type 1 T-ALLs exhibited overexpression of IL7R, its ligand HGF, and repressors of cytokine signaling (SOCS1, SOCS2, SOCS3) which regulates the IL7R pathway via negative feedback loop. Deconvolution analysis of ATAC-Seq profiles showed that T-ALLs later developing into type-1 relapses resembled a predominant immature thymic T-cell population, whereas T-ALLs developing into type-2 relapses resembled a mixture of normal T-cell precursors. Moreover, an analysis of remission samples revealed a significant enrichment of mutations in constitutional cancer predisposition genes (CPG) in type 2 patients, thus indicating fundamental differences between these two groups of patients. In both types of relapse, we observed known and novel drivers of drug resistance including MDR1 and MVP and NT5C2.

Conclusion

In sum, our comprehensive analyses revealed fundamentally different mechanisms driving either type-1 or type-2 T-ALL relapse and indicate that differential capacities of disease evolution are already inherent to the molecular setup of the initial leukemia. Leukemias of patients with type-1 relapses were often characterized by upregulation of the IL7R pathway, whereas type-2 relapses were characterized by (i) an enrichment of TAL-1 fusion, (ii) and of constitutional mutations in CPG, (iii) divergent genetic and epigenetic remodeling, and (iv) an enrichment of somatic hypermutator phenotypes.

Keyword(s): Drug resistance, Epigenetic, Genomics, Relapsed acute lymphoblastic leukemia

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: S108

Type: Oral Presentation

Session title: From biology to preclinical models in ALL

Background
Relapse is the main cause of death from pediatric acute precursor T-cell leukemia (T-ALL), but the underlying mechanisms of disease evolution from initial disease to relapse remain incompletely understood and show remarkable interpatient heterogeneity.

Aims
As cross-sectional studies failed to identify unifying determinants of relapse, we adopted a longitudinal strategy and performed multi-omic analyses in 13 matched pairs of initial diagnosis and relapse samples and their matched PDXs. We extended this set by WES and methylome analyses in an additional cohort of 25 matched DNA samples from patient cells collected at initial diagnosis, remission, and relapse.

Methods
Thirty-eight patients were recruited from the ALL‐BFM 2000/2009, CoALL97/03/09, and ALL‐REZ BFM 2002 trials or from Schneider Children’s Medical Center of Israel at time points of initial diagnosis, remission, and relapse. Material from 13 matched pairs of PDXs (RNA, cells) was used for multi-omic analyses, including DNA-Seq (WES), RNA-Seq, ATAC-Seq and methylation analysis with EPIC arrays.

Results

Based on the profile of SNVs and InDels we distinguished 18 (47%) type-1 (derived from the major ancestral clone) and 20 (53%) type-2 relapses (derived from a minor ancestral clone). We observed stronger remodeling on the way to type 2 than to type 1 relapses reflected by more evident changes in methylation, chromatin accessibility and gene expression. At the time of relapse, 3/20 type 2 patients exhibited a hypermutator phenotype, probably caused by gains of mutations in TP53, BLM and BUB1B combined with PMS2. Moreover, type 2 T-ALLs were predominantly TAL1-driven (4/8) in contrary to type 1 (0/5). T-ALLs that later progressed to type-2 relapses exhibited a complex subclonal architecture, unexpectedly, already at the time of initial diagnosis. The fraction of subclonal mutations of those T-ALLs that later developed into a type-2 relapse was significantly higher already at the time of initial diagnosis than in those T-ALLs that later developed into a type-1 relapse (p=0.0387; Fisher’s exact), a difference that became even more pronounced at the time of relapse (p<0.0001). On the other hand, relapse type 1 T-ALLs exhibited overexpression of IL7R, its ligand HGF, and repressors of cytokine signaling (SOCS1, SOCS2, SOCS3) which regulates the IL7R pathway via negative feedback loop. Deconvolution analysis of ATAC-Seq profiles showed that T-ALLs later developing into type-1 relapses resembled a predominant immature thymic T-cell population, whereas T-ALLs developing into type-2 relapses resembled a mixture of normal T-cell precursors. Moreover, an analysis of remission samples revealed a significant enrichment of mutations in constitutional cancer predisposition genes (CPG) in type 2 patients, thus indicating fundamental differences between these two groups of patients. In both types of relapse, we observed known and novel drivers of drug resistance including MDR1 and MVP and NT5C2.

Conclusion

In sum, our comprehensive analyses revealed fundamentally different mechanisms driving either type-1 or type-2 T-ALL relapse and indicate that differential capacities of disease evolution are already inherent to the molecular setup of the initial leukemia. Leukemias of patients with type-1 relapses were often characterized by upregulation of the IL7R pathway, whereas type-2 relapses were characterized by (i) an enrichment of TAL-1 fusion, (ii) and of constitutional mutations in CPG, (iii) divergent genetic and epigenetic remodeling, and (iv) an enrichment of somatic hypermutator phenotypes.

Keyword(s): Drug resistance, Epigenetic, Genomics, Relapsed acute lymphoblastic leukemia

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