Mapping AML heterogeneity – multi-cohort transcriptomic analysis identifies novel clusters and divergent ex-vivo drug responses

medRxiv

Abstract

Abstract Subtyping of acute myeloid leukaemia (AML) is predominantly based on recurrent genetic abnormalities, but recent literature indicates that transcriptomic phenotyping holds immense potential to further refine AML classification. Here we integrated five AML transcriptomic datasets with corresponding genetic information to provide an overview (n=1224) of the transcriptomic AML landscape. Consensus clustering identified 17 robust patient clusters which improved identification of CEBPA -mutated patients with favourable outcomes, and uncovered transcriptomic subtypes for KMT2A rearrangements (2), NPM1 mutations (5), and AML with myelodysplasia-related changes (AML-MRC) (5). Transcriptomic subtypes of KMT2A , NPM1 and AML-MRC showed distinct mutational profiles, cell type differentiation arrests and immune properties, suggesting differences in underlying disease biology. Moreover, our transcriptomic clusters show differences in ex-vivo drug responses, even when corrected for differentiation arrest and superiorly capture differences in drug response compared to genetic classification. In conclusion, our findings underscore the importance of transcriptomics in AML subtyping and offer a basis for future research and personalised treatment strategies. Our transcriptomic compendium is publicly available and we supply an R package to project clusters to new transcriptomic studies.

Authors 11

1. Jeppe F. Severens corresponding Aachen Department of Biomedical Data Sciences Leiden Center for Computational Oncology

   Leiden University Medical Center · Delft University of Technology

   Affiliation as printed

   Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands

   Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, The Netherlands

   Pattern Recognition & Bioinformatics, Delft University of Technology, Delft, The Netherlands

2. Emin Onur Karakaslar Aachen Department of Biomedical Data Sciences Leiden Center for Computational Oncology

   Leiden University Medical Center · Delft University of Technology

   Affiliation as printed

   Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands

   Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, The Netherlands

   Pattern Recognition & Bioinformatics, Delft University of Technology, Delft, The Netherlands

3. Bert A. van der Reijden

   Radboud University Nijmegen · Radboud University Medical Center

   Affiliation as printed

   Laboratory of Hematology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

4. Elena Sánchez‐López Aachen Center for Proteomics and Metabolomics Leiden Center for Computational Oncology

   Leiden University Medical Center

   Affiliation as printed

   Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands

   Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, The Netherlands

5. Redmar R. van den Berg Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

6. Constantijn J.M. Halkes Aachen Department of Hematology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands

7. Peter van Balen Aachen Department of Hematology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands

8. Hendrik Veelken Aachen Department of Hematology, Leiden University Medical Center Leiden Center for Computational Oncology

   Leiden University Medical Center

   Affiliation as printed

   Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands

   Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, The Netherlands

9. Marcel J. T. Reinders Aachen Department of Biomedical Data Sciences Leiden Center for Computational Oncology

   Leiden University Medical Center · Delft University of Technology

   Affiliation as printed

   Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands

   Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, The Netherlands

   Pattern Recognition & Bioinformatics, Delft University of Technology, Delft, The Netherlands

10. Marieke Griffioen Aachen Department of Hematology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands

11. Erik B. van den Akker Aachen Department of Biomedical Data Sciences Leiden Center for Computational Oncology

    Leiden University Medical Center · Delft University of Technology

    Affiliation as printed

    Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands

    Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, The Netherlands

    Pattern Recognition & Bioinformatics, Delft University of Technology, Delft, The Netherlands