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Hematopoiesis is a highly regulated process that, starting from hematopoietic stem cells (HSCs) with self-renewal capacity in the adult human bone marrow, is able to generate all different types of mature blood cells. The classical view of hematopoiesis defines binary branching points from these HSCs that segregate lineages and direct differentiation to terminally differentiated functional cell types [1]. However, the described hierarchical model can be complemented with the emerging data that suggest the existence of hematopoietic stem and progenitor cells with a continuum of transitory differentiation stages, including cells with early lineage priming that generate distinct blood cell types according to the physiological or pathological environment [2]. In this context, there are increasing data of hematopoietic plasticity and cell lineage conversion, particularly in leukemogenesis. Examples of transdifferentiation include B-cell lymphomas that can transform to histiocytic/dendritic cell sarcoma, erythroid/megakaryocytic lineages changing to granulomonocytic-like lineage upon use of a histone demethylase LSD1 inhibitor or B-ALL (acute lymphoblastic leukemia) patients that evaded CD19-directed antibody therapy (blinatumomab) by undergoing myeloidlineage switch. Related to the latter scenario, lineage switching has also been reported as a cause of antigen loss in chimeric antigen receptor T-cell therapies, where B-ALL patients transdifferentiate in their relapse as acute myeloblastic leukemia in response to the initial CD19-directed immunotherapy [3]. Due to the central role of epigenetics, particularly DNA methylation, in the successful generation of differentiated blood cell types and its plasticity during lineage specification [4], we wondered about its function in hematopoietic transdifferentiation, a largely unexplored field. Our studied model of transdifferentiation is a welldefined experimental system that converts B cells into macrophages. Following initial work that demonstrated that normal murine B-cell precursors as well as mature antibody-producing B cells can be induced by C/EBPα to transdifferentiate into functional macrophages [5], a murine cellular model was established of pre-B cells containing a fusion of C/EBPα with the estrogen receptor hormone binding domain (C/EBPαER) that converts them to macrophage-like cells upon 17β-estradiol exposure [6]. We have recently translated this model to human B-lymphoma and leukemia cell lines that can be induced by C/EBPα to transdifferentiate into functional macrophages [7]. Importantly, primary human BCR-ABL1(+) B-ALL cells could also be induced to reprogram into macrophage-like cells by transient expression of C/EBPα [8]. To explore the changes * Manel Esteller mesteller@carrerasresearch.org

B-cell leukemia transdifferentiation to macrophage involves reconfiguration of DNA methylation for long-range regulation