Lineage Switching in Acute Leukemias: A Consequence of Stem Cell Plasticity?

Abstract

<jats:p>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.</jats:p>

Mixed phenotype acute leukaemia: a case report of an unusual presentation

“…9 MPALs are thought to arise from multipotent progenitor stem cells which can differentiate into lymphoid and myeloid lineages. 10 Several diagnostic criteria have been proposed to distinguish MPAL from acute leukaemia with aberrant expression of differentiation antigens from another lineage.…”

Adult NK lineage development in humans is strengthened upon emergency

“…Moreover, ALL relapse often display lineage switching or mixed phenotypes, though the involved mechanisms are still poorly understood [9] . Our recent studies have shown that TLR stimulation on cell precursors within leukemic BM does not account for leukemic cell progression, but innate immune cell production, including functional NK cells, is promoted [10] .…”

“…Concomitant production of pro-inflammatory cytokines upon external microbial insults, and leukemia cells-derived endogenous cytokines might exert synergy favoring quiescence exit [11] , proliferation, mobilization and differentiation [12] of normal clones towards innate immune cells. During chronic exposure, exhaustion of normal residual hematopoiesis could represent a risk factor [9,13] and (Vilchis-Ordoñez et al, in revision).…”

Uncovering a new cellular origin for acute myeloid leukemia with lineage plasticity

“…2 Acute leukemias can also switch their lineage during treatment-associated relapse, showing that hematopoietic malignancies can have transdifferentiation potential. 3,4 It has been assumed that leukemias with lineage infidelity and switching capacity arise upon malignant transformation of a HSC, which has stable multipotent lineage differentiation potential; however, the cellular origin of both phenomena has not yet been identified.…”