RUNX1 mutations in blast-phase chronic myeloid leukemia associate with distinct phenotypes, transcriptional profiles, and drug responses

• DOI: 10.1038/s41375-020-01011-5
• Publication Date: 2020-08-11T17:05:34Z
• Authors: Shady Adnan Awad; Olli Dufva; Aleksandr Ianevski; Bishwa Ghimire; Jan Koski; Pilvi Maliniemi; Daniel Thomson; Andreas Schreiber; Caroline A. Heckman; Perttu Koskenvesa; Matti Korhonen; Kimmo Porkka; Susan Branford; Tero Aittokallio; Matti Kankainen; Satu Mustjoki
• Keywords: PROGNOSIS; Drug Resistance; RAG-MEDIATED RECOMBINATION; AML; core binding factors; RUNX1 MUTATIONS; Molecular Targeted Therapy; Chronic; Gene Editing; 0303 health sciences; Tumor; Leukemia; Disease Management; Flow Cytometry; Combined Modality Therapy; 3. Good health; Phenotype; Core Binding Factor Alpha 2 Subunit; Disease Susceptibility; Cancers; STEM-CELLS; Signal Transduction; Protein Binding; GENETICS; 610; acute myeloid leukemia; Article; Cell Line; Immunophenotyping; Ikaros Transcription Factor; 03 medical and health sciences; Cell Line, Tumor; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Exome Sequencing; Biomarkers, Tumor; Humans; SIGNATURES; Binding Sites; ta3122; TRANSFORMATION; Drug Resistance, Neoplasm; Mutation; T-CELLS; Neoplasm; BCR-ABL Positive; Transcriptome; Blast Crisis; Biomarkers; RESISTANCE; Gene Deletion; Myelogenous

AbstractBlast-phase chronic myeloid leukemia (BP-CML) is associated with additional chromosomal aberrations,RUNX1mutations being one of the most common. Tyrosine kinase inhibitor therapy has only limited efficacy in BP-CML, and characterization of more defined molecular subtypes is warranted in order to design better treatment modalities for this poor prognosis patient group. Using whole-exome and RNA sequencing we demonstrate thatPHF6andBCORL1mutations,IKZF1deletions, and AID/RAG-mediated rearrangements are enriched inRUNX1mutBP-CML leading to typical mutational signature. On transcriptional level interferon and TNF signaling were deregulated in primaryRUNX1mutCML cells and stem cell and B-lymphoid factors upregulated giving a rise to distinct phenotype. This was accompanied with the sensitivity ofRUNX1mutblasts to CD19-CAR T cells in ex vivo assays. High-throughput drug sensitivity and resistance testing revealed leukemia cells fromRUNX1mutpatients to be highly responsive for mTOR-, BCL2-, and VEGFR inhibitors and glucocorticoids. These findings were further investigated and confirmed in CRISPR/Cas9-edited homozygousRUNX1−/−and heterozygousRUNX1−/mutBCR-ABL positive cell lines. Overall, our study provides insights into the pathogenic role ofRUNX1mutations and highlights personalized targeted therapy and CAR T-cell immunotherapy as potentially promising strategies for treatingRUNX1mutBP-CML patients.