RUNX1 mutations in blast-phase chronic myeloid leukemia associate with distinct phenotypes, transcriptional profiles, and drug responses
Funding Information: Conflict of interest SM has received honoraria and research funding from Novartis, Pfizer and Bristol-Myers Squibb (not related to this study). SAA has received research funding from Incyte. SB is a member of Member of the advisory board of Qiagen, Novartis, and Cepheid and has received research funding from Novartis, honoraria from Novartis, Qiagen, Cepheid, and Bristol-Myers Squibb and support from the National Health and Medical Research Council of Australia APP1117718 and APP1104425, the Ray and Shirl Norman Cancer Research Trust, and the Royal Adelaide Hospital Research Foundation. The other authors declare that they have no conflict of interest. Funding Information: Funding This work was supported by Academy of Finland (Grant No. 292605 and 287224), the Finnish Funding Agency for Innovation (Dnro 6113/31/2016), Finnish special governmental subsidy for health sciences, research and training, Signe and Ane Gyllenberg Foundation, Finnish Cultural Foundation, Nordic Cancer Union, Helsinki Institute of Life Science, Cancer Foundation Finland, Relander Foundation, Incyte Nordic Hematology grant, and Finnish Cancer Institute. Publisher Copyright: © 2020, The Author(s). ; Blast-phase chronic myeloid leukemia (BP-CML) is associated with additional chromosomal aberrations, RUNX1 mutations 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 that PHF6 and BCORL1 mutations, IKZF1 deletions, and AID/RAG-mediated rearrangements are enriched in RUNX1mut BP-CML leading to typical mutational signature. On transcriptional level interferon and TNF signaling were deregulated in primary RUNX1mut CML cells and stem cell and B-lymphoid factors upregulated giving a rise to distinct phenotype. This was accompanied with the sensitivity of RUNX1mut blasts to CD19-CAR T cells in ex vivo assays. High-throughput drug sensitivity and resistance testing revealed leukemia cells from RUNX1mut patients to be highly responsive for mTOR-, BCL2-, and VEGFRinhibitors and glucocorticoids. These findings were further investigated and confirmed in CRISPR/Cas9-edited homozygous RUNX1−/− and heterozygous RUNX1−/mut BCR-ABL positive cell lines. Overall, our study provides insights into the pathogenic role of RUNX1 mutations and highlights personalized targeted therapy and CAR T-cell immunotherapy as potentially promising strategies for treating RUNX1mut BP-CML patients. ; Peer reviewed