Abstract
Simple SummaryAcute lymphoblastic leukemia is a heterogeneous disease characterized by a diversity of genetic alterations, following a sophisticated and controversial organization. In this review, we present and discuss the concepts exploring the cellular, molecular and functional heterogeneity of leukemic cells. We also review the emerging evidence indicating that cell plasticity and oncogene-induced reprogramming should be considered at the biological and clinical levels as critical mechanisms for identifying and targeting leukemia-initiating cells.Our understanding of the hierarchical structure of acute leukemia has yet to be fully translated into therapeutic approaches. Indeed, chemotherapy still has to take into account the possibility that leukemia-initiating cells may have a distinct chemosensitivity profile compared to the bulk of the tumor, and therefore are spared by the current treatment, causing the relapse of the disease. Therefore, the identification of the cell-of-origin of leukemia remains a longstanding question and an exciting challenge in cancer research of the last few decades. With a particular focus on acute lymphoblastic leukemia, we present in this review the previous and current concepts exploring the phenotypic, genetic and functional heterogeneity in patients. We also discuss the benefits of using engineered mouse models to explore the early steps of leukemia development and to identify the biological mechanisms driving the emergence of leukemia-initiating cells. Finally, we describe the major prospects for the discovery of new therapeutic strategies that specifically target their aberrant stem cell-like functions.
Highlights
Cell plasticity is a property required for cell reprogramming
The concept of the stability of stem cell function has been challenged by the finding that only the Oct4, Sox2, c-Myc and Klf4 transcription factors are required for the reprogramming of somatic cells into induced pluripotent stem cells [1]
Driven by the immunoglobulin heavy-chain (IgH) locus, PAX5-ELN efficiently induced the B-acute lymphoblastic leukemia (ALL) in mice associated with the acquisition of secondary mutations in genes involved in the JAK/STAT and RAS/MAPK pathways, which are recurrently found in B-ALL patients [162] and in other oncogene-induced B-ALL models such as ETV6RUNX1 [185] and TCF3-PBX1 [186] transgenic mice
Summary
Cell plasticity is a property required for cell reprogramming. The specification of cellular fate during development and differentiation is a dynamic and evolving process that initiates in stem/progenitor cells. The phenotypic characterization of LSCs in the original studies led to the idea that AML is organized in a hierarchical pattern, in a way similar to that of normal hematopoiesis and derive from the malignant transformation of a primitive hematopoietic cell [8,9] Supporting this notion, some murine leukemia models have led to show that AML-initiating mutations occur at the level of HSCs and alter their self-renewal properties [10,11]. Pioneering works and emerging studies converge around the notion that the biological properties of pre-leukemic and/or leukemic stem cells, including oncogene-induced reprogramming, cell plasticity, sustained self-renewal activity, cell-quiescence and drug-resistance, can significantly affect leukemia treatment and should be considered in the search for new and more targeted therapies. We describe the perspectives for the identification of new therapeutic agents that target their aberrant stem cell-like functions
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