RUNX1mutations in blast-phase chronic myeloid leukemia associate with distinct phenotypes, transcriptional profiles, and drug responses

Show full item record



Permalink

http://hdl.handle.net/10138/333455

Citation

Awad , S A , Dufva , O , Ianevski , A , Ghimire , B , Koski , J , Maliniemi , P , Thomson , D , Schreiber , A , Heckman , C A , Koskenvesa , P , Korhonen , M , Porkka , K , Branford , S , Aittokallio , T , Kankainen , M & Mustjoki , S 2021 , ' RUNX1mutations in blast-phase chronic myeloid leukemia associate with distinct phenotypes, transcriptional profiles, and drug responses ' , Leukemia , vol. 35 , pp. 1087–1099 . https://doi.org/10.1038/s41375-020-01011-5

Title: RUNX1mutations in blast-phase chronic myeloid leukemia associate with distinct phenotypes, transcriptional profiles, and drug responses
Author: Awad, Shady Adnan; Dufva, Olli; Ianevski, Aleksandr; Ghimire, Bishwa; Koski, Jan; Maliniemi, Pilvi; Thomson, Daniel; Schreiber, Andreas; Heckman, Caroline A.; Koskenvesa, Perttu; Korhonen, Matti; Porkka, Kimmo; Branford, Susan; Aittokallio, Tero; Kankainen, Matti; Mustjoki, Satu
Contributor organization: Department of Clinical Chemistry and Hematology
University of Helsinki
Helsinki University Hospital Area
HUS Comprehensive Cancer Center
Department of Oncology
TRIMM - Translational Immunology Research Program
Hematologian yksikkö
Research Programs Unit
Digital Precision Cancer Medicine (iCAN)
Computational Systems Medicine
Institute for Molecular Medicine Finland
Helsinki Institute of Life Science HiLIFE
Department of Medicine
Tero Aittokallio / Principal Investigator
Bioinformatics
HUSLAB
Date: 2021-04
Language: eng
Number of pages: 13
Belongs to series: Leukemia
ISSN: 0887-6924
DOI: https://doi.org/10.1038/s41375-020-01011-5
URI: http://hdl.handle.net/10138/333455
Abstract: Blast-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 inRUNX1(mut)BP-CML leading to typical mutational signature. On transcriptional level interferon and TNF signaling were deregulated in primaryRUNX1(mut)CML cells and stem cell and B-lymphoid factors upregulated giving a rise to distinct phenotype. This was accompanied with the sensitivity ofRUNX1(mut)blasts to CD19-CAR T cells in ex vivo assays. High-throughput drug sensitivity and resistance testing revealed leukemia cells fromRUNX1(mut)patients 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(-/mut)BCR-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 treatingRUNX1(mut)BP-CML patients.
Subject: RAG-MEDIATED RECOMBINATION
RUNX1 MUTATIONS
STEM-CELLS
T-CELLS
AML
TRANSFORMATION
RESISTANCE
SIGNATURES
PROGNOSIS
GENETICS
3122 Cancers
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


Files in this item

Total number of downloads: Loading...

Files Size Format View
s41375_020_01011_5.pdf 3.035Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record