Abstract
Switches from the lymphoid to myeloid lineage during B-cell precursor acute lymphoblastic leukemia (BCP-ALL) treatment are considered rare and thus far have been detected in MLL-rearranged leukemia. Here, we describe a novel BCP-ALL subset, switching BCP-ALL or swALL, which demonstrated monocytosis early during treatment. Despite their monocytic phenotype, ‘monocytoids’ share immunoreceptor gene rearrangements with leukemic B lymphoblasts. All swALLs demonstrated BCP-ALL with CD2 positivity and no MLL alterations, and the proportion of swALLs cases among BCP-ALLs was unexpectedly high (4%). The upregulation of CEBPα and demethylation of the CEBPA gene were significant in blasts at diagnosis, prior to the time when most of the switching occurs. Intermediate stages between CD14negCD19posCD34pos B lymphoblasts and CD14posCD19negCD34neg ‘monocytoids’ were detected, and changes in the expression of PAX5, PU1, M-CSFR, GM-CSFR and other genes accompanied the switch. Alterations in the Ikaros and ERG genes were more frequent in swALL patients; however, both were altered in only a minority of swALLs. Moreover, switching could be recapitulated in vitro and in mouse xenografts. Although children with swALL respond slowly to initial therapy, risk-based ALL therapy appears the treatment of choice for swALL. SwALL shows that transdifferentiating into monocytic lineage is specifically associated with CEBPα changes and CD2 expression.
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Acknowledgements
This work was supported by grants: Sciex 09.043 (LS), NT 12397-4 (EF), GAUK 914613 (LS), GACR P301/10/1877 and NT13462 (EM). The FACS Aria instrument was supported by EU-Prague project CZ.2.16/3.1.00/24022, FWvD was supported by the Kay Kendall Leukaemia Fund and ZZ was supported by RVO-VFN64165/2012. This work was also supported by the project for conceptual development of research organization 00064203 and CZ.2.16/3.1.00/24022.We thank Alzbeta Vazna for sequencing; Iveta Janotova for data management; Veronika Kanderova for performence of the in vitro experiments; Pavel Semerak for technical assistance in sorting; Daniel Thurner, Angela Schumich and Daniela Morf for processing of FC samples; Katerina Muzikova for PCR analyses of sorted samples; and the Czech Pediatric Hematology Group for collaboration (Doctors Sterba, Timr, Mihal, Cerna, Prochazkova, Blazek and Hak) and for providing clinical information (Doctors. Timr, Smisek, Votava and Hak).
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LS analyzed the 8CSAC combination and performed in vitro and in vivo experiments, methylation analyses and MRD examinations; JS designed the analysis of methylation status, and was involved in the design of in vitro experiments and their interpretation and designed the expression studies; EF was responsible for the MRD examinations and expression studies; EV evaluated the morphology; JV performed the MLPA; MZ, FWvD and JZ performed the SNP arrays; LR performed a part of the expression studies, ZZ was responsible for the cytogenetics; KP designed and performed the expression array, GC performed the expression studies; MF interpreted the methylation studies; TK designed the sorting; KF analyzed the profiling data; JPB designed the in vivo experiments and performed the investigations of the Swiss patient; BB executed the xenograft model; MND performed the investigations of the Austrian patients; JT supervised the molecular genetics; JS managed the patients and contributed to data collection; OH wrote and reviewed the manuscript and EM discovered the key aspects of the switching phenomenon, identified the swALL patients, designed the research, analyzed the data and wrote the manuscript. All authors have read and approved the submission of the manuscript.
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Slamova, L., Starkova, J., Fronkova, E. et al. CD2-positive B-cell precursor acute lymphoblastic leukemia with an early switch to the monocytic lineage. Leukemia 28, 609–620 (2014). https://doi.org/10.1038/leu.2013.354
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DOI: https://doi.org/10.1038/leu.2013.354