Abstract

Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.

In chronic myeloid leukaemia (CML), the drivers of blast crisis and resistance to tyrosine kinase inhibitors are not fully characterised. Here, the authors analyse a cohort of CML samples with genomic technologies and find that at least one driver alteration is associated with progression and worse prognosis.

Details

Title
Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia
Author
Ochi Yotaro 1   VIAFID ORCID Logo  ; Yoshida Kenichi 2 ; Ying-Jung, Huang 3 ; Ming-Chung, Kuo 4 ; Nannya Yasuhito 2 ; Sasaki, Ko 5   VIAFID ORCID Logo  ; Mitani Kinuko 5   VIAFID ORCID Logo  ; Hosoya Noriko 6   VIAFID ORCID Logo  ; Hiramoto Nobuhiro 7 ; Ishikawa Takayuki 7 ; Branford, Susan 8 ; Shanmuganathan Naranie 9   VIAFID ORCID Logo  ; Ohyashiki Kazuma 10 ; Takahashi, Naoto 11   VIAFID ORCID Logo  ; Takaku Tomoiku 12 ; Tsuchiya Shun 12 ; Kanemura Nobuhiro 13 ; Nakamura, Nobuhiko 13   VIAFID ORCID Logo  ; Ueda Yasunori 14 ; Yoshihara Satoshi 15 ; Bera Rabindranath 4 ; Shiozawa Yusuke 2 ; Zhao, Lanying 16 ; Takeda, June 2 ; Watatani Yosaku 2 ; Okuda Rurika 2 ; Makishima Hideki 2 ; Shiraishi Yuichi 17 ; Chiba Kenichi 17 ; Tanaka, Hiroko 17   VIAFID ORCID Logo  ; Sanada Masashi 18   VIAFID ORCID Logo  ; Takaori-Kondo Akifumi 19   VIAFID ORCID Logo  ; Miyano Satoru 17 ; Ogawa Seishi 20 ; Lee-Yung, Shih 4   VIAFID ORCID Logo 

1  Graduate School of Medicine, Kyoto University, Department of Pathology and Tumor Biology, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033); Graduate School of Medicine, Kyoto University, Department of Hematology and Oncology, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033) 
2  Graduate School of Medicine, Kyoto University, Department of Pathology and Tumor Biology, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033) 
3  Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan (GRID:grid.454211.7) (ISNI:0000 0004 1756 999X) 
4  Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan (GRID:grid.454211.7) (ISNI:0000 0004 1756 999X); Chang Gung University, College of Medicine, Taoyuan, Taiwan (GRID:grid.145695.a) 
5  Dokkyo Medical University, Department of Hematology and Oncology, Tochigi, Japan (GRID:grid.255137.7) (ISNI:0000 0001 0702 8004) 
6  Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X); Graduate School of Medicine, The University of Tokyo, Department of Medical Genomics, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X) 
7  Kobe City Medical Center General Hospital, Department of Hematology, Kobe, Japan (GRID:grid.410843.a) (ISNI:0000 0004 0466 8016) 
8  Centre for Cancer Biology, SA Pathology, Department of Genetics and Molecular Pathology, Adelaide, Australia (GRID:grid.470344.0) (ISNI:0000 0004 0450 082X) 
9  Centre for Cancer Biology, SA Pathology, Department of Genetics and Molecular Pathology, Adelaide, Australia (GRID:grid.470344.0) (ISNI:0000 0004 0450 082X); Royal Adelaide Hospital and SA Pathology, Department of Haematology, Adelaide, Australia (GRID:grid.416075.1) (ISNI:0000 0004 0367 1221) 
10  Tokyo Medical University, Department of Hematology, Tokyo, Japan (GRID:grid.410793.8) (ISNI:0000 0001 0663 3325) 
11  Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Department of Hematology, Akita, Japan (GRID:grid.251924.9) (ISNI:0000 0001 0725 8504) 
12  Juntendo University School of Medicine, Department of Hematology, Tokyo, Japan (GRID:grid.258269.2) (ISNI:0000 0004 1762 2738) 
13  Gifu University Hospital, Department of Hematology, Gifu, Japan (GRID:grid.411704.7) 
14  Kurashiki Central Hospital, Department of Hematology and Oncology, Kurashiki, Japan (GRID:grid.415565.6) (ISNI:0000 0001 0688 6269) 
15  Hyogo College of Medicine Hospital, Department of Hematology, Nishinomiya, Japan (GRID:grid.272264.7) (ISNI:0000 0000 9142 153X) 
16  Graduate School of Medicine, Kyoto University, Department of Pathology and Tumor Biology, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033); Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033) 
17  Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X) 
18  Clinical Research Center, National Hospital Organization Nagoya Medical Center, Department of Advanced Diagnosis, Nagoya, Japan (GRID:grid.410840.9) (ISNI:0000 0004 0378 7902) 
19  Graduate School of Medicine, Kyoto University, Department of Hematology and Oncology, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033) 
20  Graduate School of Medicine, Kyoto University, Department of Pathology and Tumor Biology, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033); Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033); Centre for Haematology and Regenerative Medicine, Karolinska Institute, Department of Medicine, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-021-23097-w
ProQuest document ID
2527359664
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.