Thumbnail Image
Item

An integrative multiparametric approach stratifies putative distinct phenotypes of blast phase chronic myelomonocytic leukemia

Gurashi, K.
; 
Wang, Y. H.
; 
Amaral, F. M. R.
; 
Spence, K.
; 
Cant, R.
; 
Yao, C. Y.
; 
Lin, C. C.
; 
Wirth, C.
; 
Wedge, D. C.
; 
Montalban-Bravo, G.
... show 5 more
Citations
Google Scholar:
Lookup
Altmetric:
Abstract
Approximately 30% of patients with chronic myelomonocytic leukemia (CMML) undergo transformation to a chemo-refractory blastic phase (BP-CMML). Seeking novel therapeutic approaches, we profiled blast transcriptomes from 42 BP-CMMLs, observing extensive transcriptional heterogeneity and poor alignment to current acute myeloid leukemia (AML) classifications. BP-CMMLs display distinctive transcriptomic profiles, including enrichment for quiescence and variability in drug response signatures. Integrating clinical, immunophenotype, and transcriptome parameters, Random Forest unsupervised clustering distinguishes immature and mature subtypes characterized by differential expression of transcriptional modules, oncogenes, apoptotic regulators, and patterns of surface marker expression. Subtypes differ in predicted response to AML drugs, validated ex vivo in primary samples. Iteratively refined stratification resolves a classification structure comprising five subtypes along a maturation spectrum, predictive of response to novel agents including consistent patterns for receptor tyrosine kinase (RTK), cyclin-dependent kinase (CDK), mechanistic target of rapamycin (MTOR), and mitogen-activated protein kinase (MAPK) inhibitors. Finally, we generate a prototype decision tree to stratify BP-CMML with high specificity and sensitivity, requiring validation but with potential clinical applicability to guide personalized drug selection for improved outcomes.
Authors
Gurashi, K.
Wang, Y. H.
Amaral, F. M. R.
Spence, K.
Cant, R.
Yao, C. Y.
Lin, C. C.
Wirth, C.
Wedge, D. C.
Montalban-Bravo, G.
Colla, S.
Tien, H. F.
Somervaille, T. C. P.
Batta, K.
Wiseman, D. H.
Affiliation
Epigenetic of Haematopoiesis Group, Division of Cancer Sciences, The University of Manchester, Manchester, UK. Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. The National University Hospital of Taiwan, Taipei, Taiwan. Wedge Group, Manchester Cancer Research Centre, University of Manchester, Manchester, UK. Wedge Group, Manchester Cancer Research Centre, University of Manchester, Manchester, UK; NIHR Manchester Biomedical Research Centre, Manchester, UK. Departments of Leukemia, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA. Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK; The Christie Hospital NHS Foundation Trust, Manchester, UK. Epigenetic of Haematopoiesis Group, Division of Cancer Sciences, The University of Manchester, Manchester, UK. Electronic address: kiran.batta@manchester.ac.uk. Epigenetic of Haematopoiesis Group, Division of Cancer Sciences, The University of Manchester, Manchester, UK; The Christie Hospital NHS Foundation Trust, Manchester, UK. Electronic address: daniel.wiseman@manchester.ac.uk.
Description
Date
2025
Publisher
Collections
All Christie Publications
Show all metadata
Files
Thumbnail Image
Found in UnPaywall
Adobe PDF, 8.6 MB
Keywords
Type
Article
Citation
Gurashi K, Wang YH, Amaral FMR, Spence K, Cant R, Yao CY, et al. An integrative multiparametric approach stratifies putative distinct phenotypes of blast phase chronic myelomonocytic leukemia. Cell reports Medicine. 2025 Feb 18;6(2):101933. PubMed PMID: 39892394. Pubmed Central PMCID: PMC11866517. Epub 2025/02/02. eng.
Journal Title
Journal ISSN
Volume Title
URI
https://christie.openrepository.com/handle/10541/627496
Embedded videos