Acute leukemias are the most common cancer in childhood and characterized by the uncontrolled production of hematopoietic precursor cells of the lymphoid or myeloid series within the bone marrow. Even when a relatively high efficiency of therapeutic agents has increased the overall survival rates in the last years, factors such as cell lineage switching and the rise of mixed lineages at relapses often change the prognosis of the illness. During lineage switching, conversions from lymphoblastic leukemia to myeloid leukemia, or vice versa, are recorded. The central mechanisms involved in these phenomena remain undefined, but recent studies suggest that lineage commitment of plastic hematopoietic progenitors may be multidirectional and reversible upon specific signals provided by both intrinsic and environmental cues. In this paper, we focus on the current knowledge about cell heterogeneity and the lineage switch resulting from leukemic cells plasticity. A number of hypothetical mechanisms that may inspire changes in cell fate decisions are highlighted. Understanding the plasticity of leukemia initiating cells might be fundamental to unravel the pathogenesis of lineage switch in acute leukemias and will illuminate the importance of a flexible hematopoietic development. 1. Early Cell Fate Decisions in the Hematopoietic System: Unidirectional and Irreversible? Mature cells within the hierarchical hematopoietic system, are conventionally classified into two major lineages: lymphoid and myeloid. The lymphoid lineage consists of B, T, and natural killer (NK) cells, whereas the myeloid lineage includes erythrocytes, megakaryocytes, mast cells, granulocytes, monocytes, and macrophages. A number of subtypes of dendritic cells (DC) are generated via the pathways of lymphoid or myeloid differentiation [1–3]. Starting in the very primitive multipotential hematopoietic stem cells (HSC), lineage commitment proceeds after a gradual process of cell differentiation and concomitant series of ordered lineage exclusions. As progenitor cells progress through the pathway, their differentiation capabilities narrow, and at the point where potential limits the fate, the precursors become now-committed [4]. It is believed that once a cell is committed to a given lineage, its fate must be set due to precise combinations of lineage transcription factors and epigenetic modifications to the chromatin [5]. However, considering that hematopoiesis implies a continuing dialogue between developing cells and the surrounding microenvironmental cues [4], the unidirectional and irreversible
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