Springer Nature [academic journals on nature.com], Leukemia, 4(35), p. 1087-1099, 2020
DOI: 10.1038/s41375-020-01011-5
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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.