|Biological features of primary APL blasts: their relevance to the understanding of granulopoiesis, leukemogenesis and patient management|
|Bruno Cassinat and Christine Chomienne|
Hopital Saint-Louis, Paris, Institute of Hematology, INSERM E 00-03 France
Correspondence to: C Chomienne, INSERM E 00-03 Laboratoire de Biologie Cellulaire Hématopoïétique, Institut d'Hématologie, Hôpital Saint-Louis, 1 avenue Claude Vellefaux 75010 Paris, France
In recent years, discovery of the in vitro and in vivo differentiation of APL blasts by all-trans retinoic acid (ATRA) has modified the therapeutic approach of APL and lead to important advances in understanding the biology of APL. Since it became apparent that differentiation therapy of APL with ATRA was indeed a true model of targetted therapy, evidencing the molecular targets of retinoic acid efficacy became crucial. These molecular targets are closely related to the biological features of APL cells, some of which are well-known and have contributed to the morphological and cytogenetic definition of the leukemia, others have just been defined or re-discovered in the light of a better understanding of molecular controls of cell growth and differentiation. The aims of characterizing the biological features of APL cells should allow a better management of APL therapy and the identification of potential markers for differentiation therapies in other leukemias or solid tumors. Oncogene (2001) 20, 7154-7160.
APL blasts; differentiation; granulopoiesis; retinoids; RARa gene rearrangements
Acute promyelocytic leukemia (APL) is a morphologically, cytogenetically and clinically distinct subtype of acute myeloid leukemia (AML3) characterized by the morphology of the blast cells, a specific t(15;17) translocation and risks of coagulopathy (Bennett et al., 1976). This leukemia was further characterized by an exquisite sensitivity to all-trans retinoic acid (ATRA) and the production of a fusion gene altering the RAR and PML genes (for review Grignani et al., 1994). Other features have been described, (previously or more recently) such as variations in the cytological or immunophenotypic aspect, or novel cytogenetic and oncogenic markers. Analysis of these subtle aspects of APL are being analysed at the European and International level to define whether these novel features define different sub-groups of a same leukemia or represent distinct leukemic entities (Sainty et al., 2000; Grimwade et al., 2000)
To date, no other AML subtype responds to ATRA, confirming that differentiation therapy of APL with ATRA is indeed a true model of targetted therapy. Thus, evidencing the molecular targets of retinoic acid efficacy is crucial. These molecular targets are closely related to the biological features of APL cells, some of which are well-known and have contributed to the morphological and cytogenetic definition of the leukemia, and the discovery of its sensitivity to ATRA (morphological criteria, t(15;17) translocation and/or PML-RAR expression); others have just been defined or re-discovered either in the light of a better understanding of molecular controls of cell growth and differentiation or of retinoic acid signaling pathways.
We have recently evidenced that relapse rate of APL patients is determined by the sensitivity of the APL clone to ATRA at diagnosis (Cassinat et al., 2001). If the aim of differentiation therapy is to increase survival and achieve a cure of the disease, knowledge of the different biological features of the various APLs should allow a better targetting of APL therapy and might be transposed to other differentiation therapies in leukemias or solid tumors.
Normal myeloid features of the APL cell
In vitro differentiation of APL cells with ATRA, a model for normal granulocytic differentiation
Altered RAR receptors block normal granulocytic differentiation and arrest cells at the promyelocytic stage of myeloid differentiation (Collins et al., 1990; Parrado et al., 2000). APL, which is induced by a variety of chromosomal translocations into the retinoic acid receptor gene, are recognized cytologically by their resemblance to a promyelocyte. Apart from a specific nucleus conformation and characteristic aspect of the chromatin, the promyelocyte is characterized by 'primary' azurophilic granules that persist in decreasing numbers until the last phases of neutrophil maturation. These granules contain proteases (the group of Cathepsin G, Leucocyte Elastase and Proteinase 3/Myeloblastin) and other proteases such as myeloperoxidase and defensins. APL cells, M3-AML of the FAB classification, are hypergranular with heavy azurophilic granules, bundles of Auer rods (faggots) and a reniform or bilobed nucleus (Bennett et al., 1976). The proteases contained in the granules may activate coagulation pathways and lead, when released by the APL cells, to disseminated intravascular coagulation or fibrinolysis (Dombret et al., 1993). APL cells express at their cell surface proteins which are expected in the normal promyelocyte and are usually CD34-, CD38-, CD33+, CD13+, CD45+ and HLA-DR-, a classical pattern of expression, useful for diagnosis (Paietta et al., 1994). These cells have no function of a differentiated granulocyte.
Primary cultures of APL blasts allow to evidence the in vitro differentiation process from the promyelocyte to the neutrophil. After 6 days in culture in the presence of all-trans RA 10-7 M, more than 90% of the leukemic clone present phenotypic features of mature granulocytes at the band or fully segmented neutrophil stage. As the promyelocyte undergoes transition to the myelocyte and through to the neutrophil, it acquires specific granules and reduces its number of primary granules. These specific granules contain in their matrix and on their membrane, the proteins required for a differentiated granulocyte's function. Thus a terminally differentiated APL cell displays neutrophil functions required for phagocytosis, chemotaxis, and respiratory burst function.
Thus, the in vitro differentiation of APL cells, allows to mimic normal promyelocytic differentiation. This results in a decrease of Cathepsin G (Seale et al., 1996), and Myeloblastin (Belaaouaj et al., 1999), a concomitant increase of the C/EBP gene, which regulates most genes of the specific granule proteins (Morosetti et al., 1997; Park et al., 1999) and a subsequent expression of genes coding for molecules linked with cell adhesion, such as specific integrins (CD11b, CD18), E-selectin ligand (CD15), leucocyte alkaline phosphatase (Garattini et al., 1996) and cytokine receptors, such as GM-CSF receptors or G-CSF receptors (Chomienne et al., 1990; De Gentile et al., 1994). Like normal activated neutrophils, differentiated APL cells synthesize and secrete cytokines such as IL-8, IL-1 and IL-6 or TNF- (Dubois et al., 1994).
This in vitro model has indeed proved useful to identify novel parameters such as the identification of specific calcium pumps, SERCA (Launay et al., 1999), annexins (Chang et al., 1992) or the study of transcriptional proteins of granulopoiesis or RA signalisation (Delva et al., 1999). Though most RA-target genes in myelopoiesis have been identified in human or mice leukemic cell lines, their normal function is usually confirmed in mice models (Ward et al., 2000). It may be pertinent to test if these targets are determinant for the APL cell's response to various therapeutic agents.
Abnormal features of the APL cell
Potential handicaps for maximal APL cell differentiation and patient long-term survival
Unquestionably, this differentiation process is occurring in a malignant cell, where, despite some remaining functional pathways, various abnormal proteins may disorganize or completely impede either the differentiation process or other potential targeted therapies. This may be generalized to specific APL subtypes or be specific of a given patient's clone. These altered pathways may explain some of the clinical symptoms of APL, the side-effects observed with ATRA and/or differences in ATRA sensitivity of the APL cells. Though these abnormalities may be multiple and not frequent, their knowledge is directly implicated in the understanding of the leukemogenesis of APL, and the management of ATRA therapy. To date different features have been listed, with as yet no apparent link, despite multiple correlation studies. Interestingly, most of these features, which are reviewed below, have been identified as prognostic parameters for the APL patients.
Since, 1976 specific morphological subtypes had been evidenced by the French American British (FAB) cooperative group (Bennett et al., 1976). Indeed compared to the classical, M3-AML, a cytological hypogranular or microgranular variant form, M3v, has been identified that is devoid of granules or contain only a few fine azurophilic granules. Rare cases characterized by hyperbasophilic microgranular blast cells with cytoplasmic budding mimicking micromegacaryocytes or with M1 or M2-like morphology are also described (Neame et al., 1997; Allford et al., 1999). A recent study defines the morphological criteria of APL blasts with PLZF-RAR fusions and reports a predominance of blasts with regular nuclei and an increased number of Pelger-like cells. Amongst the different differentiation antigens studied, only the expression of CD56 appeared highly correlated with this rare type of APL (Sainty et al., 2000). Likewise, classical M3-AML may present with differences in their immunophenotypic pattern. CD34 APL cases are not rare and have been correlated with the M3 variant phenotype (Guglielmi et al., 1998; Exner et al., 2000; Foley et al., 2001). Expression of lymphoid antigens like CD2 and CD19 (Guglielmi et al., 1998), or the natural killer-associated antigen CD56 (Exner et al., 2000) are also found, the latter being correlated with poor prognostic (Ferrara et al., 2000).
The t(15;17) translocation is the prevalent chromosomal translocation in APL (Larson et al., 1984). The PML-RAR fusion gene resulting from the t(15;17) translocation is of schematically three types, depending on the breakpoint in the PML gene on chromosome 15. The frequency of the different subtypes is approximately of 60% for BCR1, 35% for BCR3 and 5% for BCR2. BCR1 and BCR3 oncogenes present similar transcriptional activities and ligand binding affinities for ATRA (review Grignani et al., 1994). No knowledge concerning the half-life of these proteins, their phosphorylated state or binding with the co-repressors is apparently available in the literature. It may, however, be suspected that as the distal region of exon 6, which is sometimes lost in the BCR2 subtype and always deleted in the BCR3 subtype, is rich in serine-proline residues, differences in the phosphorylated state of these proteins may be expected. Likewise, this exon contains the caspase cleavage site of PML and may explain why the BCR3 subtype is resistant to RA-induced degradation in vitro (Slack et al., 1997). Their prognostic significance in APL remains controversial. This is probably related to the small cohorts studied and should be clarified in the near future. In some difficult cases, despite optimal experimental conditions, the classical t(15;17) is not evidenced by cytogenetics and the translocation is only evidenced by FISH or RT-PCR (this situation was evaluated by the European Working Party to represent 5.4% of cases) (Grimwade et al., 2000). The reciprocal RAR-PML gene is not detected in all patients. Interestingly the APL blasts of a patient who only expressed the reciprocal fusion and not PML-RAR did not differentiate with ATRA in vitro (Grimwade et al., 2000). Recent studies in transgenic mice, would confirm data from patient studies that the presence of the reciprocal oncogene enhances the leukemic aggressiveness (Pollock et al., 2000).
Other chromosomal translocations implicating the RAR gene are reported in APL, though in very small percentages. In the study of the European Working Party, 60 cases of APL without the classical t(15;17) were evidenced. Eleven cases were positives for the t(11;17) translocation and PLZF/RAR (Grimwade et al., 2000). Interestingly, five out of five PLZF-RAR patients blasts did not differentiate in vitro with ATRA 10-6 mol/l as previously reported (Guidez et al., 1994; Licht et al., 1995), and no ATRA syndrome was reported for these patients, consistent with the hypothesis that this latter phenomenon is associated with cytokine release during differentiation of the leukemic clone. t(5;17) translocations are rare and their response to ATRA unclear; the number of documented patients scarce and only partial responses recorded despite in vitro differentiation of fresh APL blasts at high doses of ATRA (10-6 M) (Redner et al., 1996). The STAT5b/RAR fusion was evidenced in one APL patient, and no response to ATRA was obtained (Arnould et al., 1999). The incidence of secondary chromosomal abnormalities in APL varies in the different reported series, with a proportion of around 30%, but does not appear to confer a poor prognosis (Slack and Yu, 1998; De Botton et al., 2000).
One deregulated pathway which has yet not been deciphered is that leading to the elevated white blood cell count (hyperleucocytosis) observed in some APL cases (Fenaux et al., 1999). Hyperleucocytosis remains the major prognostic factor of APL (Fenaux et al., 1999) as it frequently enhances the risk of coagulopathy due to the increased release of leucocyte proteases. No specific biological features of the APL cell seems to determine this phenomenon though it has been associated with the AML3 cytological variant, the expression of CD13, CD2, ICAM-1 and the Bcr3 PML-RAR subtype (review Chomienne et al., 1996; Hsu et al., 1999). The expression of these different proteins involved in cell-cell interaction and migration, has lead to the hypothesis that their expression on APL cells may enhance the trans-endothelial migration of the APL cells from the bone marrow to the peripheral blood.
Hyperleucocytosis is also induced or enhanced by ATRA therapy (Fenaux et al., 1999; Warrel et al., 1993). In these cases in vitro proliferation of the APL cell is observed, along with an increased secretion of IL-1 and G-CSF (Chomienne et al., 1990, Dubois et al., 1994). Secretion of G-CSF by the blasts may further increase its migration from the bone marrow to the peripheral blood and leukocyte activation. ATRA differentiated APL cells express and secrete in vitro molecules of leukocyte activation (such as integrins, IL-6 and IL-8, TNF-, and IL-1) (Dubois et al., 1991, 1994). This may engender the symptoms of the ATRA syndrome which are reminiscent of those observed in the endotoxic shock syndrome and in the adult respiratory distress syndrome (ARDS) (De Botton et al., 1998). However, no specific biological feature of an APL cell allows prediction of either hyperleucocytosis or the ATRA syndrome.
Although neutrophils are known to be eliminated from the peripheral blood by apoptosis, and HL-60 cells treated by ATRA produce up to 40% of apoptotic cells (Martin et al., 1990), ATRA fails to induce apoptosis in vitro in fresh APL cells (Tosi et al., 1994; Calabresse et al., 1995), despite extinction of BCL2 expression (Calabresse et al., 1995) and induction of apoptotic genes (Altucci et al., 2001). Apoptotic pathways are nevertheless functional in fresh APL cells as more potent apoptotic drugs such as the retinoid (CD437), the topoisomerase II inhibitor, or Arsenic, can effectively induce apoptosis in vitro (Calabresse et al., 1995; Mologoni et al., 1999; Niu et al., 1999). These surprising data suggest that anti-apoptotic features in APL cells, such as the PML-RAR protein (review Grignani et al., 1994) or growth factors (Dubois et al., 1991), may prevent effective induction of apoptosis in vitro by ATRA and that endogenous in vivo parameters may contribute to the elimination of the APL cells. However, it is known that ATRA therapy alone cannot eliminate the leukemic clones (Warrel et al., 1993) and means to effectively monitor in vitro and in vivo the induction of successful apoptosis of the differentiated APL blasts would permit better control of the full eradication of the disease.
In vitro differentiation of the APL blasts has on the other hand always been exquisitely correlated with the in vivo efficacy in terms of achievement of complete remission (Chomienne et al., 1990; Warrel et al., 1993). We have, however, recently evidenced that a poor in vitro sensitivity to ATRA at diagnosis is correlated to Event Free Survival, relapse rate and long-term survival (Cassinat et al., 2001). We had previously reported in small cohorts, a great heterogeneity in ATRA sensitivity from one patient to another, evidenced on the oxydo-reduction function, cytokine expression and intracellular ATRA concentrations (Agadir et al., 1995a; Dubois et al., 1991) suggesting that some APL clones can not achieve terminal differentiation. Likewise ATRA-differentiated APL cells in vitro and in vivo have been reported to be deficient for secondary granules (Miyauchi et al., 1997). These inter-patient differences in differentiation achievement may reflect the presence of distinct altered pathways. Our study did not allow to correlate the in vitro sensitivity with biological features of the APL cell such as CD2, CD13 expression or high WBC count, though a trend with PML-RAR subtype and the AML cytological variant may be interesting to pursue in a bigger cohort. Gallagher et al. (1995) had previously reported a weaker differentiating response of the BCR2 PML-RAR subtype. This novel prognostic factor underlines the importance of defining these various altered pathways and optimizing ATRA's mechanism of action in the APL cell in the hope that it may still by-pass most of these altered pathways.
Retinoic acid signaling pathways in APL cells
The control of gene expression through nuclear receptors requires both receptor interaction with promoter DNA sequences and regulatory proteins which transduce transcriptional initiation (or inhibition) signals to the basal transcription machinery. Regulatory proteins, such as the nuclear receptor co-activators, interact with nuclear receptors and modulate the transcriptional responsiveness to ligand through transactivation domains. The effect of retinoic acid is mediated by its binding to specific retinoic acid receptors RARs, RXRs and CRABPs (review Chambon, 1996). APL cells express, predominantly the PML-RAR genes and to a lesser extent RXR, RAR, RAR and CRABPII (review Grignani et al., 1994; Agadir et al., 1995b; Delva et al., 1999, and personal data from the laboratory).
In the presence of high concentrations of ATRA, PML-RAR can activate RA-inducible reporter genes (review Grignani et al., 1994; Rousselot et al., 1994; Park et al., 1999). This is in agreement with the structural conservation of the ligand binding domain in the PML-RAR protein and a lower binding affinity of all-trans RA to APL cell endogenous RA-receptors compared to HL-60 cell endogenous receptors (Agadir et al., 1995b). Functional PML-RAR may be crucial as patients with mutations in the RAR portion are less sensitive to ATRA and prone to relapse. Indeed such mutations have been reported in ATRA resistant subclones of the APL cell line NB4 (Shao et al., 1997; Kitamura et al., 1997; Duprez et al., 2000) but also, more interestingly, in patients with clinical resistance to ATRA at relapse (Imaizumi et al., 1998; Ding et al., 1998). The mutations were probably acquired because they were not detected at the initial onset of APL, although it cannot be excluded that the mutated clone was initially present and selected by therapy as resistant to ATRA. Distinct mutations were found in those patients, all of them located in the ligand binding region of RAR leading to a decrease of the ligand dependant transcriptional activity of the mutant PML-RAR. Of note, mutations were always found in the fusion and never in the corresponding sequence of the normal RAR allele.
In fresh APL cells, ATRA up-regulates some of the RA signaling genes such as CRABPII (Delva et al., 1999), RAR and RAR (Chomienne et al., 1991; Agadir et al., 1995b). These up-regulations are rapid and transcriptionally regulated, whereas subsequent decrease of RAR or PML-RAR are post-transcriptional and related to proteasome degradation (Zhu et al., 1999), as also noted after differentiation of APL cells via CD44 activation (Charrad et al., 1999) or for other hematopoietic oncogenes or transcriptional proteins such as AML1-ETO or ETO (Da Silva et al., 2000) once differentiation is achieved. Most other RA-target genes, such as C/EBP (Morosetti et al., 1997) have been studied in cell lines, but have not to date been reported on fresh APL cells (Altucci et al., 2001).
Functional activation of the nuclear receptors is known to depend on a number of partners. In the absence of ATRA, the heterodimer (RAR/RXR) binds DNA and represses transcription through its association with corepressors involved in a multicomponent repressor complex (Heinzel et al., 1997). The differences in the dissociation rate of PML-RAR and PLZF-RAR from the co-repressors suggests that the partners of RAR in the different chromosomal translocations must certainly play a role (Guidez et al., 1998; He et al., 1998). Likewise, the normal function of PML and PLZF, which is altered in the APL cell, is not, as yet, fully understood. Nevertheless, it is interesting to note that PML is necessary for RA differentiation and participates in the retinoic acid nuclear receptor complex (Wang et al., 1998). PLZF is also a nuclear protein which is down-regulated during granulocytic differentiation (Parrado et al., 2000). Thus complete or partial restoration of these proteins may be important for maximal efficacy of ATRA, and may explain why other APL subtypes are less sensitive to ATRA.
Pharmacodynamic studies of retinoic acid in the APL cell reflects the cascade of protein interactions involved in RA signaling. It has in the past been evidenced the specific structure-dose response of fresh APL cells compared to HL-60 cell line in reference to its lack of sensitivity to 13-cis RA (review Chomienne et al., 1996). Primary cultures of APL blasts reflect the sensitivity of the retinoic acid nuclear complex to different retinoids. Intracellular concentrations of ATRA in fresh APL cells allows to predict ATRA response in vitro and in vivo (Agadir et al., 1995a,b). However, little is known about the exact physiological outcome of ATRA in normal myeloid cells or APL patients. Different enzymes are implicated in the conversion of the exogenous vitamin A to retinoic acid and its various metabolites (Napoli, 1996). These enzymes depend on the presence of cytochrome P450, NAD and certain cellular binding proteins such as CRABP which act as substrate and carrier for retinoic acid during its metabolism. Polymorphisms of the enzymes of cytochrome P450 may also reflect in vivo heterogeneity of ATRA concentrations and/or efficacy. Secondary resistance to ATRA was only observed in the first APL trials when ATRA was given continuously for several months. This resistance was related to a feed back mechanism that progressively reduces plasma concentrations of ATRA (Muindi et al., 1992). In these circumstances, CRABPII which acts as a ligand-binding co-activator of the nuclear receptors is increased to compensate for the reduced ATRA levels (Delva et al., 1993, 1999). This syndrome is no longer observed as clinical trials propose either short (one month) ATRA induction therapy or sequential maintenance ATRA therapy, and all patients who relapse after ATRA therapy can now obtain a second complete remission (Thomas et al., 2000).
Improvement of APL differentiation: How to tackle APL's molecular targets?
One major target is ATRA's signaling pathways. Improving the pharmacodynamics of ATRA may accelerate the differentiation of the leukemic clone. Agents which either have a higher affinity for the receptors (such as RAR agonists), or may aim at higher intracellular concentrations of RA such as liposomal preparations (Douer et al., 2001), have been shown in vitro to be more potent than ATRA and to have similar effects at least for achievement of CR in patients. Early studies on leukemic cell differentiation had evidenced that combination with drugs such as sodium butyrate, cytosine arabinoside or cyclic AMP primed the leukemic cell lines for ATRA differentiation. This priming effect is now explained by the roles played by these agents on transcription: gene methylation (aracytine, hydroxyurea), protein phosphorylation (cyclic AMP), or acetylation of histones (sodium butyrate). Because of the involvement of HDAC in the repression of transcription in APL cells, inhibitors of HDAC are supposed to have potential interest in APL treatment. Several classes of HDAC inhibitors have been described (sodium butyrate, Trichostatin A or TSA, suberoylanilide hydroxamic acid or SAHA, etc.) (Marks et al., 2000) and some of them have been shown to induce growth arrest, differentiation or apoptosis in various cancer cells in vitro. In PML-RAR and PLZF-RAR expressing cells, the association of HDAC inhibitors with ATRA potentiates ATRA induced differentiation and restores ATRA sensitivity in ATRA resistant cells (He et al., 1998; Lin et al., 1998). In vivo efficacy of combination of sodium butyrate with ATRA has already been reported in one relapsed and ATRA resistant APL patient (Warrel et al., 1998) but it was not confirmed in four additional patients (Novitch et al., 1999).
Targeting other differentiation pathways in combination with ATRA may prove equally effective. In vitro association with Interferon or G-CSF (Cassinat et al., 1998; Chelbi-Alix and Pelicano, 1999) has been shown promising, and some APL patients have been reported to benefit in vivo from the association (Jansen et al., 1999). As normal differentiation follows a multistep process, maximal differentiation of the leukemic cell may also be expected to follow a similar route and combination of differentiation inducers may be needed to either prime or induce terminal differentiation. Recently Charrad et al. (1999) have identified a third target for leukemic cell differentiation, through activation of the CD44 protein, expressed on leukemic cells. CD44 is already know to be involved in normal myelopoiesis, and efficacy in leukemic cells again underlines that normal differentiation agents and pathways are functional in a leukemic cell (Sachs, 1978). This approach has not been as yet transposed in vivo but the in vitro data showing differentiation of fresh APL cells comparable to ATRA pushes to believe that in vivo efficacy may be expected. Combination of both pathways may enhance the differentiation effect.
The combined efficacy of cytotoxic drugs such as daunorubicin or cytosine-arabinoside with differentiation drugs has now been shown to be beneficial for the survival of APL patients (Fenaux et al., 1999). Other routes to eliminate the leukemic cells may be studied, and used alone or in association with ATRA to enhance the anti-leukemic efficacy. Induction of apoptosis may be encountered with cytotoxic drugs in low concentrations but the novel use of AS2O3 has recently been shown to be effective alone (Niu et al., 1999) or when combined to ATRA (Lallemand-Breitenbach et al., 1999).
Nevertheless, targeting the functional cellular pathways of apoptosis or differentiation may not always be possible in a given leukemic clone, some leukemic cells may overpass our current knowledge of physiological pathways. Therefore, targeting specific proteins expressed by the leukemic cell may be more effective. Along this line, the CD33 differentiation protein, also expressed on the APL cell, has been targeted by monoclonal antibody and cell lysis mediated by an isotope (Jurgic et al., 1995). The PML-RAR oncogene may equally be addressed as leukemic target, either by inhibiting its expression through antisens oligonucleotides, ribozymes or tyrosine kinase inhibitors or by stimulating the patient's immune system through DNA or peptide vaccination. Preclinical assays in mice with mutated oncogenes show promising results. Intramuscular injection of a nude DNA plasmid containing the oncogene generates both specific cellular and humoral responses, allowing to reduce tumor burden (Gjersten et al., 1995). This promising therapy requires a somewhat functional immune system and may be more useful as a complement to maintenance therapy when the patient is in complete remission.
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