Journal
LEUKEMIA
Volume 28, Issue 3, Pages 609-620Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2013.354
Keywords
minimal residual disease; lineage switch; CCAAT/ enhancer-binding protein alpha; acute lymphoblastic leukemia; Monocytes; CD2 Antigen
Categories
Funding
- EU [CZ.2.16/3.1.00/24022]
- Kay Kendall Leukaemia Fund
- project for conceptual development of research organization [CZ.2.16/3.1.00/24022, 00064203]
- [Sciex 09.043]
- [NT 12397-4]
- [GAUK 914613]
- [GACR P301/10/1877]
- [NT13462]
- [RVO-VFN64165/2012]
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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 CEBPa 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 CD14(neg)CD19(pos)CD34(pos) B lymphoblasts and CD14(pos)CD19(neg)CD34(neg) '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 CEBPa changes and CD2 expression.
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