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Integrated analysis of relapsed B-cell precursor Acute Lymphoblastic Leukemia identifies subtype-specific cytokine and metabolic signatures.

ABSTRACT: Recent efforts reclassified B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) into more refined subtypes. Nevertheless, outcomes of relapsed BCP-ALL remain unsatisfactory, particularly in adult patients where the molecular basis of relapse is still poorly understood. To elucidate the evolution of relapse in BCP-ALL, we established a comprehensive multi-omics dataset including DNA-sequencing, RNA-sequencing, DNA methylation array and proteome MASS-spec data from matched diagnosis and relapse samples of BCP-ALL patients (n?=?50) including the subtypes DUX4, Ph-like and two aneuploid subtypes. Relapse-specific alterations were enriched for chromatin modifiers, nucleotide and steroid metabolism including the novel candidates FPGS, AGBL and ZNF483. The proteome expression analysis unraveled deregulation of metabolic pathways at relapse including the key proteins G6PD, TKT, GPI and PGD. Moreover, we identified a novel relapse-specific gene signature specific for DUX4 BCP-ALL patients highlighting chemotaxis and cytokine environment as a possible driver event at relapse. This study presents novel insights at distinct molecular levels of relapsed BCP-ALL based on a comprehensive multi-omics integrated data set including a valuable proteomics data set. The relapse specific aberrations reveal metabolic signatures on genomic and proteomic levels in BCP-ALL relapse. Furthermore, the chemokine expression signature in DUX4 relapse underscores the distinct status of DUX4-fusion BCP-ALL.

SUBMITTER: Schroeder MP

PROVIDER: S-EPMC6414622 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Integrated analysis of relapsed B-cell precursor Acute Lymphoblastic Leukemia identifies subtype-specific cytokine and metabolic signatures.

Schroeder Michael P MP Bastian Lorenz L Eckert Cornelia C Gökbuget Nicola N James Alva Rani AR Tanchez Jutta Ortiz JO Schlee Cornelia C Isaakidis Konstandina K Häupl Björn B Baum Katharina K Migueles Lozano Oscar Arturo OA Kouidri Khouloud K Pan Kuan-Ting KT Urlaub Henning H Schwartz Stefan S Burmeister Thomas T von Stackelberg Arend A Hoelzer Dieter D Pfeiffer Heike H Rieger Michael A MA Göllner Stefanie S Oellerich Thomas T Horstman Martin M Schrappe Martin M Wolf Jana J Kirschner-Schwabe Renate R Brüggemann Monika M Müller-Tidow Carsten C Serve Hubert H Neumann Martin M Baldus Claudia D CD

Scientific reports 20190312 1

Recent efforts reclassified B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) into more refined subtypes. Nevertheless, outcomes of relapsed BCP-ALL remain unsatisfactory, particularly in adult patients where the molecular basis of relapse is still poorly understood. To elucidate the evolution of relapse in BCP-ALL, we established a comprehensive multi-omics dataset including DNA-sequencing, RNA-sequencing, DNA methylation array and proteome MASS-spec data from matched diagnosis and relaps ...[more]

PMID: 30862934

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Project description:On July 11, 2017, the Food and Drug Administration granted approval for blinatumomab for the treatment of relapsed or refractory (R/R) precursor B-cell acute lymphoblastic leukemia (ALL). Blinatumomab is a bispecific CD19-directed CD3 T-cell engager. The basis for the approval included results from two clinical trials, TOWER and ALCANTARA. TOWER, a randomized trial comparing overall survival in patients with Philadelphia chromosome (Ph)-negative R/R ALL receiving blinatumomab versus standard-of-care (SOC) chemotherapy, demonstrated a hazard ratio of 0.71 favoring blinatumomab (p = .012; median survival, 7.7 months with blinatumomab and 4.0 months with SOC chemotherapy). Complete remission (CR) rates were 34% for patients receiving blinatumomab and 16% for those receiving SOC. Adverse events were consistent with those observed in prior trials, with cytokine release syndrome and some neurologic events, including tremor, encephalopathy, peripheral neuropathy, and depression, observed more frequently in the blinatumomab arm, whereas neutropenia and infection were less common among patients receiving blinatumomab. Depression emerged as a rare but potentially severe neurologic event associated with blinatumomab. In ALCANTARA, a single-arm trial of blinatumomab in patients with Ph-positive R/R ALL, the CR rate was 31%, and adverse events were similar to those observed previously in Ph-negative R/R ALL. These results support conversion from accelerated to regular approval of blinatumomab for R/R ALL and broadening of the intended population to include both Ph-positive and Ph-negative precursor B-cell R/R ALL. IMPLICATIONS FOR PRACTICE: In TOWER, a randomized trial in patients with relapsed or refractory Philadelphia chromosome (Ph)-negative precursor B-cell acute lymphoblastic leukemia (ALL), treatment with blinatumomab showed superiority over conventional chemotherapy for complete remission (CR) rate (34% vs. 16%) and survival (3.7-month improvement in median; hazard ratio, 0.71). In ALCANTARA, a single-arm trial of blinatumomab for treatment of relapsed or refractory Ph-positive precursor B-cell ALL, the CR rate was 31%. Blinatumomab is now approved for treatment of relapsed or refractory precursor B-cell ALL that is Ph positive or Ph negative.

Dataset Information

Integrated analysis of relapsed B-cell precursor Acute Lymphoblastic Leukemia identifies subtype-specific cytokine and metabolic signatures.

Publications

Integrated analysis of relapsed B-cell precursor Acute Lymphoblastic Leukemia identifies subtype-specific cytokine and metabolic signatures.

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