Research review paperNatural compounds and pharmaceuticals reprogram leukemia cell differentiation pathways
Introduction
Acquiring a specific cell function likely constitutes one of the most complex biological processes. Cell differentiation requires the accurate and coordinated regulation of the expression of many genes at the spatial and temporal levels. In addition to the control of the expression of specific genes, the management of cell proliferation and survival is crucial to generate functional cells. All biomolecules that exist in a cell are involved in differentiation processes, including transcription and chromatin remodeling factors, as well as non-coding RNAs such as micro(mi)RNAs and long non-coding (lnc)RNAs, which interact in a very complex regulatory network that manages gene expression. Together, the effectors of cell regulation interact and lead to the ultimate stage of differentiation in a stepwise manner.
In addition to the deregulation of cell proliferation and survival, the consecutive absence of normal differentiation characterizes most malignant cells. Therefore, the molecular mechanisms involved in the differentiation process have been considered a potential therapeutic target in tumor cells. Pre-clinical models were developed as early as the 1980s (Reiss et al., 1986), and the concept of concomitantly inducing cancer cell differentiation and cell proliferation arrest has become an alternative to cytotoxic chemotherapies. The aim was to modulate signaling pathways and the expression of specific genes to lead cancer cells towards a more advanced stage of differentiation and invert the growth/differentiation plot. Rather than killing cells via the activities of cytotoxic and unselective drugs, this therapy aimed to reprogram malignant and useless cells into functional ones using subtoxic doses of differentiating agents. The induction of tumor cell differentiation has been shown to be effective in the in vitro and in vivo treatments of several types of cancer cells (Leszczyniecka et al., 2001), and differentiation-inducing therapy was recently proposed to treat malignant gliomas (Liu et al., 2010). A variety of compounds that can induce cancer cell differentiation have been reported for three decades. Compounds with various molecular structures, including retinoic acid (Breitman et al., 1980, Castaigne et al., 1990), butyrate derivatives (Newmark et al., 1994), dimethyl sulfoxide (Breitman, Selonick, 1980), and anthracyclines (Morceau et al., 1996a, Sato et al., 1992, Trentesaux et al., 1993), displayed differentiation activities in vitro in leukemia cells via diverse mechanisms of action. The primary effective compounds, described as differentiation-inducing agents, were vitamin D derivatives, retinoid, interferon and polar-planar compounds. Most of these molecules were particularly active on myeloid leukemia cells, which differentiated into morphologically and functionally mature cells (Paquette and Koeffler, 1992).
Leukemia is a cancer that affects the blood, bone marrow and lymphoid system as well as the differentiation of normal hematopoietic cells. Four main types of leukemia have been determined based on the cell lineage transformation and clinical features, namely acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL). Moreover, a group of French, American and British (FAB) hematologists divided acute leukemia into subtypes; in 1976, this effort led to a classification based on the quantification of blasts, their degree of maturity and the identification of chromosomal abnormalities. Later, the World Health Organization (WHO) established a new classification based on the FAB guidelines, and this classification considered morphology as well as cytogenetic, molecular genetic, gene mutation and clinical features (Rulina et al., 2010). Molecular and cellular features in leukemia cells result from the perturbation of the normal hematopoiesis regulatory network.
Hematopoiesis is a process that leads to the continuous production and replacement of all blood cells. During embryogenesis, hematopoiesis takes place in the blood islands of the yolk sac and in the liver, spleen and lymph nodes. In adults, it occurs only in the bone marrow of sternal bones, the iliac crest and the femoral head. A small population of bone marrow cells, hematopoietic stem cells (HSC), produces hematopoietic cells in adults. HSCs are undifferentiated and multipotent cells with an increased capacity for self-renewal, proliferation and differentiation.
Most blood cells are highly differentiated with reduced protein synthesis and cell division capacity. Their lifetime varies from a few hours for neutrophils and few days for platelets to several weeks for red blood cells. Blood cells are the terminal and functional elements of the two major hematopoietic lineages, lymphoid and myeloid. The different hematopoietic cells proliferate, differentiate and complete their maturation in the bone marrow prior to entering the bloodstream and exert their function in tissues. T cells are an exception because they mature in the thymus, lymph nodes and spleen.
The regulation of the self-renewal, proliferation and differentiation of these cells involves cell–cell interactions with stromal cells from the bone marrow as well as multiple types of molecules that act in a time- and concentration-dependent manner, including cytokines, chemokines, growth factors and transcription factors (Broxmeyer et al., 1989, Broxmeyer et al., 2005, Wickrema and Crispino, 2007), as well as miRNAs (Mathieu and Ruohola-Baker, 2013). The following description of hematopoiesis regulation is not exhaustive because only the versatile roles of some transcription factors are shown. The deregulation of this network clearly perturbs hematopoiesis, which leads to hematological disorders, including leukemia. The GATA family of transcription factors has emerged as an essential regulator of gene expression in the different hematopoietic cell types. Three of the six members, GATA-1, GATA-2 and GATA-3, are expressed and functional in hematopoietic cells, whereas GATA-4, GATA-5 and GATA-6 are expressed in different tissues derived from the mesoderm and endoderm, such as the heart, liver, lung, gonads, and intestine (Molkentin, 2000). GATA-1 plays a crucial role in the suitable development of erythroid cells, especially during the later stages (Pevny et al., 1995), as well as during the differentiation of megakaryocytes, eosinophils and mast cells (Harigae et al., 1998, Hirasawa et al., 2002, Romeo et al., 1990). This zinc finger protein contains a N-terminal region, which confers transcriptional activity, and a C-terminal domain that allows binding to DNA and other proteins. GATA transcription factors specifically recognize the G/A/T/A sequence in the cis-regulatory regions of genes. GATA-binding sites are largely represented in most erythroid-related promoter/enhancer genes, including globins, heme metabolism enzymes, glycophorine A (GPA) and erythropoietin receptor (EpoR), as well as in the anti-apoptotic Bcl-xL gene (Gregory et al., 1999). Moreover, GATA-binding sites are present in the promoters of genes that are specifically involved in megakaryocyte differentiation, such as CD42a/glycoprotein (GP)9, GP2b and the thrombopoietin receptor CD110/c-Mpl (Szalai et al., 2006). GATA-1 can interact with other nuclear proteins via its C-terminal domain, resulting in the activation or repression of target gene expression in erythroid (Song et al., 2004) and megakaryocytic (Elagib et al., 2003) differentiation. The interaction of GATA-1 with its cofactor “Friend of GATA” (FOG)-1 is essential for the success of erythropoiesis and megakaryopoiesis (Dore and Crispino, 2011, Tsang et al., 1997). Other studies have shown that a factor involved in chromatin remodeling, NuRD, interacts with the N-terminus of FOG-1 and that this interaction is important for the activation or repression of genes regulated by the GATA-1/FOG-1 complex (Miccio et al., 2010, Vicente et al., 2012). The interaction between GATA-1 and NuRD/FOG-1 is required for the proper development of megakaryocytes. In addition to FOG-1, many proteins interact and form complexes around GATA-1 to modulate its transcriptional activity. LMO2 (Lim-only protein 2) is a “zinc finger” protein that can interact with GATA-1, Tal-1 (T-cell acute lymphocytic leukemia 1 protein), TCF3 (E2A immunoglobulin enhancer binding factoring E12-/E47) and LDB1 (LIM domain-binding protein 1) to form a protein complex that activates the transcription of erythroid target genes (Wadman et al., 1997). In this complex, Tal-1 is essential for erythroid and megakaryocytic developments (Wen et al., 2011). The post-translational modification of GATA-1 is reportedly important for its transcriptional activity. Immunoprecipitation experiments on the nuclear extracts of erythroid cells showed that GATA-1 can interact with CREB-binding protein (CBP)/p300 (Blobel et al., 1998). The p300 protein exerts associated acetyltransferase activity and acetylates GATA-1, required for DNA binding and transcriptional activation. The other member of the GATA family of proteins, GATA-2, cooperates with GATA-1 in a dynamic model of hematopoiesis control (Ferreira et al., 2005). At the early stages of erythroid differentiation, GATA-2 can activate the transcription of the GATA-1 gene, while GATA-1 expression represses the GATA-2 gene during development (Bresnick et al., 2010, Ikonomi et al., 2000a, Ikonomi et al., 2000b). Interestingly, GATA-1 and GATA-2 regulate their own gene expression. GATA-2 overexpression results in the megakaryocytic differentiation of cells to the detrimental erythroid lineage and is expressed in mast cells, and megakaryocytes, as well as non-hematopoietic embryonic stem cells. In addition to its role in regulating differentiation pathways, GATA-2 is expressed early in HSCs, where it plays an important role in the activation of cell proliferation.
The E26 transformation-specific (ETS) transcription factor PU.1/SPi1 is a key hematopoietic regulator that plays a specific role in myeloid and lymphoid differentiation. The expression level of PU.1 varies dynamically during hematopoiesis to guide the HSCs to one or the other hematopoietic differentiation pathway. PU.1 is overexpressed in B-cells and macrophages, whereas it is expressed at lower levels in mature erythroid cells, megakaryocytes and T cells. The inappropriate expression of PU.1 in hematopoietic-specific cells may lead to leukemic transformation, as is the case in T-cell lymphomas or erythroleukemia (Moreau-Gachelin et al., 1996, Rosenbauer et al., 2004). Studies have shown that GATA-1 and PU.1 can physically interact and inhibit each other via the N-terminal and C-terminal part of PU.1 and the C-terminal region of GATA-1. The N-terminal region of PU.1, but not the C-terminal one, is required to specifically block the binding of GATA-1 to DNA (Zhang et al., 2000). Thus, the differential activities of transcription factors can determine the commitment of cells in a specific differentiation pathway. Fli-1 and GA binding protein (BP)-α, which both belong to the ETS family of transcription factors, likely play a role in the fate of the differentiation of megakaryo-erythroid progenitors. Fli-1 is a positive regulator of megakaryopoiesis (Hart et al., 2000), whereas it negatively regulates erythroid differentiation (Athanasiou et al., 2000). GABP-α is a specific regulator of genes expressed during the early stages of megakaryopoiesis. It regulates the expression of the integrin αIIb/β3 and the CD110/c-Mpl genes (Pang et al., 2006). The ratio GABP-α/Fli-1 decreases during maturation, and this decrease correlates well with the regulation of the expression of early genes by GABP-α and late genes by Fli-1. Ets-1 is overexpressed during megakaryocyte development. Its overexpression in CD34+/HSCs results in the megakaryocytic differentiation to the detrimental erythropoiesis lineage (Dore et al., 2012).
The proto-oncogene c-Myb is an essential regulator of hematopoiesis and affects the growth, survival, proliferation and differentiation of hematopoietic cells. C-Myb plays a critical role in the commitment of stem cells to the erythroid or megakaryocytic pathway, and its interaction with GATA-1 ensures proper megakaryocytic differentiation. C-Myb factor also influences the progenitors in this differentiation pathway, but in contrast to GATA-1, c-Myb does not affect terminal differentiation (Garcia et al., 2011). Its expression is elevated in colony forming units-erythroid (CFU-E) and erythroblasts. In erythroleukemia cells that are blocked at the CFU-E stage, c-Myb can act as an inhibitor of terminal erythroid differentiation (Vegiopoulos et al., 2006).
The versatile activity of transcription factors described here reflects the complexity of the regulatory network, including further transcription factors and cofactors, miRNAs and lncRNAs, that manages hematopoietic cell differentiation and proliferation programs. The disruption of a connection in this network can lead to the deregulation of hematopoiesis and lead to hematological disease, including leukemia.
In addition to pharmaceuticals, a wide variety of plant-derived compounds (phytochemicals) can modify cell differentiation by targeting specific steps of the regulatory network. The aim of this review was to identify phytochemicals and pharmaceuticals that can induce leukemia cell differentiation. During the last two decades, various, structurally unrelated natural compounds have been investigated as differentiating agents, particularly those that act on different hematopoietic pathways as well as osteogenesis. We focused on compounds that reportedly induce the differentiation of blasts from myeloid leukemia as well as multiple myeloma (MM)-related osteogenesis (Fig. 1) because differentiation arrest is a critical feature of these cells.
Section snippets
Acute myeloid leukemia features
Acute myeloid leukemia (AML) mainly results from chromosomal translocations that produce fusion proteins with aberrant activities, which leads to the deregulation of the cell cycle and failure of hematopoietic differentiation. Clinically, the disease is associated with hyperleukocytosis, extramedullary disease and abnormal coagulation. AML is characterized by concentrations of highly proliferative myeloblastic cells in the blood or bone marrow that exceed 20%. Neoplastic cells replace normal
Chronic myeloid leukemia
Chronic myeloid leukemia is a clonal disorder of pluripotent hematopoietic stem cells characterized by an abnormal accumulation of immature leukemic blast cells in the blood, bone marrow and spleen and the blockade of the terminal differentiation of myeloid cells. Notably, leukemic cells in the blast crisis (BC) are characterized by a significant decrease in differentiation capacity. This phase of the disease features the highest number of blasts in white blood cell population and bone marrow.
Multiple myeloma and osteoblastic targets
In multiple myeloma (MM) disease, clonal malignant plasma cells that accumulate in the bone marrow reduce the bone formed by osteoblasts and stimulate bone destroyed by osteoclasts. While osteoblasts build bone by forming groups of connected cells, osteoclasts are large multinucleated cells that destroy bone. Equilibrium in the function of both cell types is critical for the maintenance and repair of compact skeletal bones. Therefore, in addition to targeting myeloma cells to treat MM patients,
Discussion and conclusion
Numerous naturally occurring molecules from the plant kingdom have interesting anti-cancer properties, including the ability to induce cell differentiation by targeting different molecular regulatory pathways (Fig. 1). The effects of various compounds on the differentiation of bone marrow-derived hematopoietic and osteogenic cells have been extensively studied. The differentiation pathways of solid tumors and tissues can also be activated by natural compounds, including adipogenesis (Jelkmann,
Acknowledgments
SC was supported by postdoctoral grants of Télévie Luxembourg. MO and AT are supported by PhD grants of Télévie Luxembourg. Research at the Laboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC) is financially supported by the “Recherche Cancer et Sang” Foundation, by the “Recherches Scientifiques Luxembourg” association, by the “Een Haerz fir kriibskrank Kanner” association, by the Action LIONS “Vaincre le Cancer” association and by Télévie Luxembourg. MD is supported by the
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2019, Biochemical PharmacologyIcariside II induces cell cycle arrest and differentiation via TLR8/MyD88/p38 pathway in acute myeloid leukemia cells
2019, European Journal of PharmacologyCitation Excerpt :Traditional Chinese medicine with abundant resources provides us a great many active components for screening. Recent years, numerous natural compounds have been identified as potential differentiating agents (Morceau et al., 2015). Icariside II (Fig. 1A), a flavonoid from Herba Epimedium koreanum Nakai, has been reported to promote osteogenic differentiation of bone marrow stromal cells (Luo et al., 2017, 2018).
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