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Differentiation induction as a treatment for hematologic malignancies Correspondence to: S Waxman, Mount Sinai School of Medicine, Box 1178, One Gustave L. The oncogenic event frequently leads to the generation of a fusion gene that facilitates proliferation by inhibiting a tumor suppressor gene and also disrupts signaling pathways required for differentiation (Melnick and Licht, 1999). In many cell lines and primary cultures derived from hematologic malignancies the malignant phenotype can be abrogated by inducing differentiation, terminal cell division or programmed cell death (apoptosis) by a variety of agents (Table 1) (Ferrari and Waxman, 1994). Interestingly, many of these agents at low concentrations induce differentiation and terminal cell division with minimal apoptosis while at higher concentration, usually by an alternative pathway, induce apoptosis with minimal evidence of differentiation (Finnin et al., 1999; Maurer et al., 1999; Richon et al., 2001; Suh et al., 1999; Wu et al., 2001). Thus, the therapeutic outcome of differentiation therapy should be correlated with measurement of differentiation, loss of clonogenicity and apoptosis. Differentiation therapy can be used with or following cycles of cytotoxic chemotherapy. This combination cytotoxic differentiation therapy results in enhanced apoptosis, prevention of regrowth of malignant cells and drug resistance and induction of differentiation specific targets, which should increase the chance for cure (Figure 1) (Hozumi, 1998; Huang and Waxman, 1998; Niitsu and Honma, 1999; Waxman, 2000; Waxman et al., 1990). In leukemic cell lines and primary cultures treatment with Biomodulators (hematopoietic growth factors, TGF, vitamin D, retinoic acid butyrates, free fatty acids, interferons) and cyclic nucleotides and Chemical agents (DMSO, histone deacetylase inhibitors (HDACi), HMBA, TPA, certain cytotoxic agents) alone, or in combination, results in a similar scenario during the process of induced differentiation. This typically includes a stochastic program of early influx of calcium, protein kinase C translocation and activation, G1 cell cycle arrest associated with p53 dependent or independent p21WAF1 induction, retinoblastoma protein hypophosphorylation, a decrease in growth associated genes such as c myc, c myb, and an early increase in anti apoptotic proteins (Rifkind et al., 1996; Scher et al., 1983b; Waxman, 2000). Thereafter an array of lineage differentiation specific gene expressions is followed by commitment to terminal cell division often with the expression of an apoptotic program (Altucci et al., 2001; Liu et al., 2000). The activation of specific signaling pathways are differentiation agent and cell type specific. Differentiation induction of hematologic malignant cells as well as normal hematopoeitic stem cell differentiation is mediated by a stochiometric ratio of transcription factors such as GATA 1 and PU 1 (Rekhtman et al., 1999) which broadly determine lineage and cooperate with more specific transcription factors such as RAR receptor and CEBP family members (Matushansky et al., 2000; Park et al., 1999; Tenen et al., 1997). Erythropoietin (EPO) induced erythrodifferentiation of leukemic cells is associated with GATA 1 induction and downregulation of PU 1 and other transcription factors that direct myeloid lineage during normal differentiation. Conversely, myeloid differentiation of A4 murine progenitor cells by GCSF or GMCSF increases RAR2 whereas erythrodifferentiation induced by EPO downregulates RAR2 (Zhu et al., 2001). Therefore, with appropriate stimulation the regulatory pathways involved in hematopoeitic differentiation can be re activated in hematopoeitic malignant cells. Targeting the molecular defect that interferes with the normal regulatory pathway may provide such a stimulus and serve as the basis of differentiation therapy. A paradigm for differentiation therapy of hematologic malignancies is provided by the successful development of all trans retinoic acid (RA) therapy and elucidation of its molecular mechanism in acute promyelocytic leukemia (APL). Differentiation therapy is effective in APL APL is a subtype of acute myeloblastic leukemia (AML) characterized by the uncontrolled expansion of promyelocytes and a block in normal granulocytic differentiation. APL provides a unique model in cancer treatment due to two significant features: (1) essentially all known cases of APL are associated with chromosomal translocations involving the retinoic acid receptor gene (RAR) (Figure 2) and (2) these patients achieve high clinical remission rates in response to differentiation therapy with all trans retinoic acid (RA), the ligand that also binds to the rearranged receptor. For many years, treatment of APL was restricted to aggressive chemotherapy that, when successful, eliminated the malignant clone. In 1988, a Chinese group reported dramatic clinical responses to oral therapy with RA, an active form of vitamin A (Huang et al., 1988). They, and subsequently researchers in France and the USA, demonstrated a novel mechanism by which these responses were obtained (Castaigne et al., 1990; Warrell et al., 1991). RA induces APL blasts to terminally differentiate along a neutrophilic pathway, without any evidence of direct cytotoxic effects. Although clinical relapse occurs commonly after treatment with RA alone, large multicenter randomized trials have demonstrated that RA in combination with chemotherapy results in a higher rate of durable remission and survival than chemotherapy alone, with a potential cure in nearly 70% of patients (Fenaux et al., 1994; Sanz et al., 2000). Thus, treatment of APL with retinoids provides the first dramatic demonstration of efficacy of differentiation therapy in an advanced malignancy. These dramatic clinical results were followed by extensive research into the mechanisms of RA induced differentiation in APL. The overwhelmingly most common translocation of APL fuses RAR with the PML gene, producing a fusion protein that has been demonstrated to cause an APL like syndrome when expressed in transgenic mice. The PML/RAR fusion protein retains most of the functional domains of both PML and RAR (Dyck et al., 1994; Weis et al., 1994). The break in RAR invariably is located within the second intron resulting in an RAR protein with only the initial A segment missing (Figure 2). The PML RAR protein acts as an aberrant retinoid receptor with additional functional properties. The dominant negative effect of the PML/RAR fusion protein on retinoid signaling has been explained at the molecular level by experiments showing more tight binding of nuclear receptor corepressors, SMRT and N CoR, to PML RAR, compared to the binding seen with RAR (Grignani et al., 1998; Lin et al., 1998). In the absence of ligand, retinoid receptors bind DNA and associate with corepressor complexes that include histone deacetylases, which keep the histones around the target gene promoter deacetylated and the chromatin in the closed conformation. In the presence of ligand corepressors dissociate from the retinoid receptors, allowing recruitment of transcriptional coactivators and activation of the transcription machinery (Figure 3). The coactivators associate with, or function as, histone acetyltransferases that cause the chromatin to adopt an open conformation allowing the initiation of target gene transcription (Grignani et al., 1998; Guidez et al., 1998; Lin et al., 1998). The PML RAR oncoprotein requires 100 higher concentration of RA for release of corepressors and recruitment of coactivators. This tighter binding of PML RAR to the corepressor complex, results in transcriptional repression at physiologic levels of RA and inactivation of critical retinoid receptor target genes in myeloid development that may be the basis for the differentiation block. The release of corepressors at pharmacologic concentrations of RA correlates well with the observed induction of differentiation in vitro and in vivo. Moreover, RA treatment results in caspase dependent PML RAR cleavage that directly removes the leukemogenic fusion gene product (Nervi et al., 1998). There is also evidence that the PML/RAR fusion gene product inhibits normal PML function, and that this may contribute to the pathogenesis of APL. The PML phosphoprotein is found in both the nucleus and the cytoplasm, but highest expression is found in PML nuclear bodies, which form a framework in the nuclear matrix that may direct chromatin folding and nucleic acid trafficking (van Driel et al., 1991). PML is believed to act as a tumor suppressor, based on reports that PML overexpression confers a growth disadvantage and suppresses transformation by cooperative oncogenes (Ahn et al., 1995; Mu et al., 1994), while PML knock out mice have increased susceptibility to infections and tumor development (Wang et al., 1998a). The PML RAR fusion protein likely disrupts the growth suppressive activity of PML, thus allowing the expansion of immature promyelocytes. This is supported by the observation that the normally punctate PML protein localization is disrupted to a microparticulate pattern by fusion to RAR in APL cells (Dyck et al., 1994; Mu et al., 1994; Weis et al., 1994). Immunohistochemical studies with both anti PML and anti RAR antibodies showed that in APL cells, PML co localizes with PML RAR and is subsequently displaced from the nuclear body structure. PML staining is returned from the microparticulate pattern to the normal discrete punctate staining after treatment with RA (Dyck et al., 1994; Weis et al., 1994). The relative importance of the restoration of RAR and PML specific pathways in RA induced differentiation is not well defined. In patients with PML RAR, pharmacologic doses of RA can convert the PML RAR protein from a dominant negative inhibitor of retinoid regulated transcription to an activator. However, RA also induces cleavage of the PML RAR protein, which appears to be required for the restoration of normal PML nuclear body structure. It is not entirely clear whether the RA induced transcriptional activity or PML RAR cleavage or both are responsible for APL cell differentiation. Mechanisms of resistance to RA induced differentiation therapy Although RA has proven to be an effective therapy for APL patients, RA treatment alone rarely induces a durable remission, and patients are often refractory to RA treatment upon relapse. Two mechanisms have been proposed to contribute to the development of RA resistance. Firstly, RA induces its own metabolic degradation, so that RA levels could be decreased to levels below the threshold for cytodifferentiation. In fact, RA resistance has been associated with reduced plasma RA concentrations. This decrease is not APL specific, as decreased plasma RA concentrations are also seen after RA treatment in patients with lung cancer or other solid tumors. However, APL blasts from RA resistant patients often fail to differentiate in vitro in response to high doses of RA, suggesting other mechanisms of resistance. Indeed, cellular retinoic acid binding proteins (CRABPs), which function to sequester and inactivate RA, have been shown to increase in APL cells with RA treatment (Cornic et al., 1994; Delva et al., 1993; Muindi et al., 1992). However, 9 cis RA, an isomer of all trans RA that maintains more stable plasma concentrations during extended treatment (Miller et al., 1995) and does not bind CRABPs, fails to reverse the acquired clinical resistance in APL patients who have been previously treated with all trans RA (Miller et al., 1995). Furthermore, synthetic RAR specific ligands not metabolized by cellular P450 enzymes are not able to overcome RA resistance in vitro or in patients (Takeuchi et al., 1998). Therefore, increasing plasma retinoid concentrations alone is not sufficient to overcome retinoid resistance, suggesting additional mechanisms for the development of RA resistance. A second hypothesis proposes genetic lesions as the cause of RA resistance. Point mutations have been identified in the ligand binding domain of the fusion gene PML RAR in cultured RA resistant APL subclones as well as in relapsed patients (Ding et al., 1998; Imaizumi et al., 1998). A mutation was reported in an RA resistant subclone that no longer responded to pharmacological concentrations of RA and functioned as a dominant negative inhibitor of RA dependent transcriptional activation, thereby blocking Moncler Jacket On Sale cytodifferentiation (Shao et al., 1997). The mutated PML RAR has lost the ability to bind ligand, and as a result constitutively associates with the corepressor SMRT and fails to interact with coactivator ACTR in a ligand dependent manner (Cote et al., 2000) (Figure 3). Other groups soon reported several mutations arising in APL cells from RA resistant patients. These mutations localize to two regions involved in forming the RA binding pocket of PML RAR and show alterations in ability to bind ligand and nuclear receptor co regulators (Kitamura et al., 1997). Finding point mutations in relapsed APL patients confirmed the results obtained in the cellular models, indicating that stable genetic lesions in the PML RAR oncoprotein account for an important mechanism mediating RA resistance. Still, not all RA resistant cell lines and relapsed APL patients harbor mutations in PML RAR, suggesting there are alternative mechanisms of RA resistance. One such mechanism may be resistance to RA induced PML RAR protein cleavage shown in some differentiation resistant APL cell lines (Jing et al., 2001). Arsenic trioxide: a second novel and highly effective therapy for APL involving differentiation Only a few years after the first reports of dramatic success of RA in the treatment of APL, Chinese researchers described the induction of remission in patients with APL using arsenic trioxide at concentrations that had limited side effects. These trials showed that arsenic induces complete remissions in 70 of newly diagnosed patients with APL and in 65 of relapsed patients (Niu et al., 1999; Shen et al., 1997). These studies have been confirmed by data from the USA showing that low doses of arsenic trioxide can induce complete remissions in relapsed APL patients (Soignet et al., 1998). Although, compared to other leukemic cell types, APL cells appear particularly sensitive to arsenic, in vitro activity in a variety of cancer cell lines has led to active clinical research in other malignancies (Chen et al., 1997; Shao et al., 1998). The mechanism of arsenic action in APL bears similarities and differences to that of RA. While RA specifically targets the aberrant fusion receptor PML/RAR, arsenic affects numerous cellular signaling pathways, and can lead to growth inhibition, the induction of apoptosis, or in some circumstances, differentiation (Chen et al., 1996; Shao et al., 1998; Wang et al., 1998b). Arsenic trioxide produces remissions in APL, at least in part, through a mechanism that results in the degradation of the PML/RAR fusion oncoprotein responsible for the development of the disease. The loss of PML/RAR releases its dominant negative block on RAR function, allowing granulocytic differentiation of the malignant clone (Figure 3). The degradation of PML/RAR protein, unlike RA, results from arsenic induced covalent modification of the PML portion of the molecule by Sumo 1, a ubiquitin like protein whose attachment may target the protein for proteasomal degradation (Zhu et al., 1997). Since modification of wildtype PML is also induced by arsenic, it is possible that alterations in the function of PML may contribute to the response to arsenic in APL cells. Although it is reasonable to assume that the release of the differentiation block by PML/RAR should lead to differentiation, the data to date are more complicated. In APL cells treated in vitro with micromolar concentrations of arsenic trioxide, which are attainable in patients, apoptosis without evidence of differentiation is observed. Indeed, when NB4 cells or fresh APL cells from untreated patients are exposed to the combination of RA and arsenic in vitro, arsenic inhibits RA induced differentiation (Jing et al., 1999; Shao et al., 1998). However, in several models of cells resistant to differentiation by RA alone, sub apoptotic concentrations of arsenic can synergize with RA to induce differentiation (Lallemand Breitenbach et al., 1999; Rego et al., 2000). When used in vivo, there is additional evidence that arsenic trioxide can induce Moncler Outlet Roma differentiation. Patients with APL, most of whom had relapsed after RA treatment, were reported to show evidence of cellular differentiation while achieving remission following arsenic treatment (Soignet et al., 1998). Mouse models of APL have also shown a possible synergy between arsenic and RA, although it has not been determined whether a sequential or a concurrent administration of the two agents is more efficient (Lallemand Breitenbach et al., 1999). Arsenic induced apoptosis, both in APL and other malignant cells occurs by a process that appears independent of its actions on the PML/RAR fusion protein (Dai et al., 1999; Davison et al., 1999). Rather, the response to As2O3 may be linked to the biochemical environment within the cell. Cancer cell lines vary substantially in their sensitivity to arsenic induced apoptosis, and there is evidence the intracellular redox and reduced glutathione (GSH) levels within a cell are predictive of arsenic responsiveness (Dai et al., 1999; Yang et al., 1999). Arsenic has been reported to inhibit glutathione reductase and decrease GSH levels within the cell (Cunningham et al., 1994). Consistent with these data, in all malignant cell models tested, arsenic induced apoptosis is enhanced by BSO, which depletes glutathione levels. Also, apoptosis is inhibited by treatments that increase cellular GSH levels. Where and how to design differentiation therapy? Therapeutic targeting of enzymes involved in aberrant transcription in APLA misuse of histone deacetylase may lead to transcriptional repression of key genes causing aberrant differentiation with uncontrolled proliferation of immature blood cells in several forms of acute myeloid leukemia (AML) associated with single chromosomal translocation. In t(8;21) AML type M 2 (Downing, 2001), the DNA binding domain of AML 1 is fused with a protein known as ETO, which Moncler Berlin interacts with co repressors associated with histone deacetylase resulting in repression of cell differentiation (Amann et al., 2001; Downing, 1999; Minucci et al., 2001) (Figure 2). Similarly, in t(12;21) (p13;q22) TEL AML 1 associated common childhood acute lymphoblastic leukemia recruits N CoR to the TEL moiety (Guidez and Zelent, 2001). In APL, in vitro and in vivo animal models demonstrate the efficacy of combining RA with HDAC inhibitors (HDACi) such as butyrates or trichostatin A for more effective differentiation induction and therapeutic response (Guidez et al., 1998; Kosugi et al., 2001; Lin et al., 1998; Warrell et al., 1998). This may relate in part to the observation that oligomerization of RAR, through a self association domain present in PML, results in an interaction with transcriptional coregulators with recruitment of histone deacetylases. This seems to be correlated and required for transcriptional repression of PML RAR target genes (Lin and Evans, 2000). Oligomerization and recruitment of HDACs may also contribute to the transformation by the AML 1 ETO fusion gene, extending these mechanisms to other forms of acute myeloid leukemias (AMLs).

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