Abstract
Unlike stem cells from solid tumors, the stem cells which initiate myelogenous leukemias arise in marrow, an organ with a unique circulation which allows ready access of leukemia cells, including leukemia stem cells (LSCs), to the vasculature. This poses unique problems in the targeting of LSCs since these cells are found circulating in the majority of leukemia cases at diagnosis and are usually not detectable during remission states. Because most cases of leukemia relapse, it is suggested that LSCs remain quiescent in the marrow until they eventually proliferate and circulate again. This indicates that effective targeting of LSCs must occur not only in peripheral circulation but in the micro-circulation of the marrow. Targeting such interactions may overcome cell adhesion-mediated treatment resistance, other multi-drug resistance mechanisms, and opportunities for clonal evolution in the marrow environment. Targeting selectins and integrins, signal transduction mediators, and chemokine/cytokine networks in the marrow micro-circulation may aid in abrogating leukemia-initiating stem cells which contribute to disease relapse. LSCs possess surface antigen profiles and signal transduction activation profiles which may allow differential targeting as compared with normal hematopoietic stem cells.
Highlights
Altman et al (2011) have found that dual targeting of mTORC1 and mTORC2 results in potent suppressive effects on primitive leukemic progenitors from AML patients
TARGETING SIGNALING PATHWAYS IN LSCs WITH SMALL MOLECULE INHIBITORS One approach to eliminating the LSC would be to target pathways regulating stem cell self-renewal, if these are differentially expressed in LSCs vs. HSCs (Rasheed et al, 2011)
Inhibitors of Wnt have been examined in CML (Baghdadi et al, 2012) and notch inhibitors have been examined in ALL, but these are toxic to normal HSCs in some cases, indicating a need to find selective inhibitors or relatively selective inhibitors for LSCs (Guzman and Jordan, 2004; Mikkola et al, 2010)
Summary
Edited by: Unlike stem cells from solid tumors, the stem cells which initiate myelogenous leukemias. Some leukemias may arise at the level of pluripotent CD33− precursors, some may have an initial mutation in a pluripotent HSC with a collaborating mutation such as a core binding factor mutation occurring later, or some may arise at the level of a committed myeloid precursor as is the case in acute promyelocytic leukemia Both the mutation(s) leading to a leukemic state and the cell of origin of the mutation are thought to have prognostic bearing (Walter et al, 2012). Bonnet and Dick (1997) found that only leukemic blasts with the immature cell-surface phenotype characterized by CD34 expression with lack of CD38 expression were capable of transferring AML to immunodeficient mice; severe combined immunodeficiency (SCID) mice This seemed consistent with a cancer stem cell (CSC) hypothesis which suggests that tumors are maintained by a small population of stem cell-like cancer cells which have the capability for indefinite self-renewal (Lapidot et al, 1994). There is evidence that pathways involved in proliferation of primitive cells such as Hox, hedgehog, notch, and www.frontiersin.org
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