The absence of CSF3R variants within the large CHIP cohort data sets published in 2014 suggest that CSF3R variants are unlikely to serve as the initiating lesion for CHIP, but the prevalence of CHIP variants such as TET2 and ASXL1 that co-occur with CSF3R variants suggests that CSF3R mutation may often be a later occurring event that imparts a neutrophilic phenotype to a preexisting CHIP process. In follow-up sequencing of an expanded cohort of 29 patients from the New England Journal of Medicine report,15 21% have exhibited both CSF3R and SETBP1 mutations, with 31% of samples having CSF3R mutations only and 7% with SETBP1 mutations only (Figure 1). Provisional diagnostic algorithm for neutrophilia and genetically informed treatment options. WHO-defined chronic neutrophilic leukemia: a long-term analysis of 12 cases and a critical review of the literature. Although the rationale for the disproportionate frequency of residue Q157 U2AF1 variants remains unclear, it is interesting to postulate that an alternately spliced gene product resulting from the variants near Q157 (but not the S34 variants) could synergize with signaling pathways that are specific to CNL and aCML, such as mutant CSF3R signaling. Molecular response of CSF3R T618I harboring chronic neutrophilic leukemia after induction chemotherapy linked to cord blood transplantation. CNL can progress to the more aggressive acute myeloid leukemia with a mean time to blast transformation of only 21 months.11 Furthermore, the median survival for patients after diagnosis was 21 or 23.5 months in 2 studies.11,12 Historically, our understanding of the genomics of CNL has been limited, with the majority of patients having normal cytogenetics.11,13 In part, the improvement of therapies for patients with CNL has been hampered by our limited understanding of the genetic and cellular underpinnings of the disease. Major criteria for CNL include >80% of the peripheral white blood cells being segmented neutrophils or bands with a total white blood cell count of ≥25 × 109/L and <10% of the white blood cells being immature granulocytic forms.8 Criteria for CNL also include hypercellularity of the marrow with <5% myeloblasts among nucleated cells, as well as normal neutrophil maturation with no granulocytic dysplasia.8 In contrast, aCML involves granulocytic dysplasia with at least 10% of peripheral white cells consisting of immature granulocytic forms (promyelocytes, myelocytes, and metamyelocytes).8 One of the challenges in the diagnosis of CNL is that many of the criteria are exclusionary. Because mutant CSF3R has been shown to lead to dysregulated JAK/STAT signaling, it has been suggested that JAK inhibitors, such as ruxolitinib, may be efficacious in treating CSF3R-mutant CNL/aCML, and a trial (NCT02092324) is currently in progress to prospectively assess this possibility. In addition, SETBP1 binds to the RUNX1 promoter and when overexpressed, it recruits the nucleosome remodeling deacetylase (NuRD) complex to the RUNX1 promoter, inhibiting transcription of this important myeloid regulator. Less than 50 cases have been reported. Diagnosing chronic neutrophilic leukemia usually begins with a visit to your family doctor or when a routine blood test suggests a problem with the blood. On the basis of high and generally similar variant allele frequencies of CSF3R, SETBP1, ASXL1, and other genetic events seen in CNL and aCML, it is highly unlikely (and in many cases impossible) that these events could be segregated into completely distinct clonal populations. Recent genomic findings in CNL and aCML have indicated that mutations may arise in at least 3 different categories of genes: epigenetic modifiers, components of the spliceosome, and growth factor signaling pathways. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Mutational events observed in epigenetic and splicing genes in CNL and aCML do not seem to be exclusive within this disease subset. In contrast, the membrane proximal mutations exhibit receptor activation in the complete absence of ligand,15,24 suggesting distinct mechanisms of activation of these classes of CSF3R mutations. Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm with a high prevalence (>80%) of mutations in the colony-stimulating factor 3 receptor (CSF3R).These mutations activate the receptor, leading to the proliferation of neutrophils that are a hallmark of CNL. Functional genomic studies will permit a more comprehensive understanding of the molecular complexity of these diseases. Cancer 1990;66:162–6 [9] Cehreli C , Undar B , Akkoc N , Onvural B , Altungoz O . Conflict-of-interest disclosure: J.G. These combinatorial mutations suggest a requirement for different therapeutic approaches tailored to the molecular profile of individual patients. The bone marrow is hypercellular, and there is no significant dysplasia in any cell lineage. Allogeneic transplantation may result in favorable long-term outcomes in selected patients, particularly when undertaken in the chronic phase of disease.1,5-7,9, Although clonality has been demonstrated in CNL,12,13 the majority of patients exhibit normal cytogenetics.1,6,7 The frequency of chromosomal changes in aCML is more variable, ranging from 20% to 88% in 4 series.5,8-10 In both diseases, trisomy 8 and del (20q) are the most common nonspecific chromosomal abnormalities observed at diagnosis or at the time of progressive disease. Acta Haematologica 1994 ; 91 : 32 – 4 In association with lambda light chain expression . Mutation of SETBP1 is prevalent in both settings, although it is apparently less restricted in these disease subsets. A recent paper described a case of a SCN patient who acquired a CSF3R truncation mutation followed by a T618I point mutation (reported as T595I using the traditional CSF3R numbering system that does not include the signal peptide).24. Neutrophilic-chronic myelogenous leukemia (CML-N) is a rare chronic myelogenous leukemia (CML) variant characterized by BCR-ABL1 positive chronic neutrophilia. These mutations can occur in isolation or in combination with other mutant genes, with 21% of patients having both CSF3R and SETBP1 mutations. Blood 2017; 129 (6): 715–722. In 2016, the WHO classification of hematologic malignancies was updated to reflect advances in our understanding of the genomics of these diseases (Table 1).38 For CNL, the presence of the CSF3R T618I mutation or other activating CSF3R mutations has become part of the diagnostic criteria.38 Patients can, however, still be classified as having CNL in the absence of a CSF3R mutation if they meet certain other criteria,38 such as having neutrophilia for at least 3 months, splenomegaly, and no detectable underlying reason for reactive neutrophilia.38 Reactive neutrophilia can be caused by an underlying infection or malignancy such as a plasma cell neoplasm.38 In the case of a plasma cell neoplasm, the diagnosis of CNL can still be made if there is evidence of myeloid cell clonality.38 The addition of CSF3R mutations to the criteria for CNL should allow for molecular in addition to phenotypic characterization of the disease entity to facilitate accurate diagnosis. Crossref Michelle A. Elliott, Ayalew Tefferi, Chronic neutrophilic leukemia: 2018 update on diagnosis, molecular genetics and management, American Journal of Hematology, 10.1002/ajh.24983, 93 , 4, (578-587), (2018). Julia E. Maxson, Jeffrey W. Tyner; Genomics of chronic neutrophilic leukemia. is supported by grants from The Leukemia and Lymphoma Society, the V Foundation for Cancer Research, the Gabrielle’s Angel Foundation for Cancer Research, the William Lawrence and Blanche Hughes Fund, and the National Cancer Institute (4 R00CA151457-03). The WHO 2008 definition of chronic neutrophilic leukemia (CNL) is based on clinical and laboratory parameters but not on molecular abnormalities. Reticulin fibrosis is not significantly increased. After decades or years of treatment with GCSF, a subset of patients with severe congenital neutropenia develop acute myeloid leukemia (AML), which is correlated with the acquisition of CSF3R truncation mutations.22 Loss of a portion of the cytoplasmic domain of the receptor can eliminate several negative regulatory motifs, depending on the precise location of the truncation mutation. To avoid infections associated with neutropenia, a large percentage of these patients are treated chronically with G-CSF to improve neutrophil production. We recently reported that ∼50% to 60% of patients with CNL or aCML harbor mutations in the receptor for colony-stimulating factor 3 (CSF3R; GCSFR).15 Among a total of 29 patients, 8 of 9 CNL (89%) and 8 of 20 aCML (40%) cases exhibited CSF3R mutations. Correlation of event-free or overall survival with other genetic features of these diseases, such as spliceosome mutations, has not yet been assessed. Abstract. Examination of the bone marrow shows a myeloid hyperplasia with full maturation with <5% myeloblasts (<1% in the peripheral blood). Neutrophilic-chronic myeloid leukemia: a distinct disease with a specific molecular marker (BCR/ABL with C3/A2 junction). Published: 25 June 2019 Blood tests make many people with leukemia nervous. Defective internalization and sustained activation of truncated granulocyte colony-stimulating factor receptor found in severe congenital neutropenia/acute myeloid leukemia. The discovery of high-frequency CSF3R mutations in CNL, and to a lesser extent in aCML, identifies a new major diagnostic criterion for these diseases and suggests a close relationship between these neutrophilic leukemias. Indeed, there is already at least 1 report of a patient who was initially diagnosed with MDS evolving to refractory anemia with excess blasts with complex karyotype without CSF3R mutation, and the disease subsequently evolved further to a phenotype resembling CNL/aCML. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. Although sample sizes were small, CNL and aCML patients who exhibited SETBP1 or ASXL1 variants were shown to exhibit worse prognosis whereas CSF3R variants were not prognostically significant. In addition, although mutations in CSF3R remain prominent events, there have been some additional instances of mutations in genes that regulate cell proliferation, growth factors, and kinase signaling. Therapy has primarily consisted of hydroxyurea or other oral chemotherapeutics, as well as interferon-α.1,5-11 These agents can elicit improvement in blood counts but exhibit no proven disease-modifying benefit. doi: https://doi.org/10.1182/blood-2013-05-500959. The pattern of mutation acquisition may, in fact, help resolve some of the contradictory reports of JAK inhibitor efficacy within this patient population. In contrast, CSF3R membrane proximal mutations strongly activate the JAK/signal transducer and activator of transcription pathway and are sensitive to JAK kinase inhibitors such as ruxolitinib. In addition, there is no dysplasia, nor clinical or molecular criteria for other myeloproliferative neoplasms. It should also be noted that the CNL sample size from which this CSF3R/U2AF1 association was made is relatively small, so the observation bears validation in larger cohorts. receive funding for administration of clinical trials from Incyte, manufacturer of ruxolitinib, and J.G. Blood samples to measure the complete blood cell counts (number and quality of white blood cells, red blood cells and platelets) As noted above, mutation of CSF3R seems to be the most common mutational event in a signaling pathway in CNL, although it is less common in aCML. Chronic Neutrophilic Leukemia: A Rare and Difficult Diagnosis of Exclusion James Ziai 1,2, Richard Torres1,2 and Christopher A. Tormey * 1Pathology and Laboratory Medicine Service, VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT 06513 ... Journal of Blood … Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm with a high prevalence (>80%) of mutations in the colony-stimulating factor 3 receptor (CSF3R). Chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (CML) are rare hematologic neoplasms that are characterized by leukocytosis and hypercellularity of … Chronic neutrophilic leukemia and multiple myeloma. The frequencies of each class of CSF3R mutation alone or in combination with SETBP1 or JAK2 are shown for a combined cohort of CNL and aCML (n = 29), the CNL cases only (n = 9), and the aCML cases only (n = 20). Correspondence: Jason Gotlib, Department of Medicine (Hematology), Stanford Cancer Institute, 875 Blake Wilbur Dr, Room 2324, Stanford, CA 94305-5821; e-mail: jason.gotlib@stanford.edu. There are at least 3 distinct models for clonal evolution and mutation acquisition that can be envisioned from the baseline, diagnostic sequencing data available to date (Figure 4). Recurrent mutations in SETBP1 were recently identified in 25% of aCML patients.17 Set binding protein (SETBP1) interacts with SET, a negative regulator of the tumor suppressor protein phosphatase 2A (PP2A).26 SETBP1 protects SET from protease cleavage, thus increasing the amount of SET available to repress the activity of PP2A.27 In AML, SETBP1 overexpression is significantly associated with reduced survival, indicating that SETBP1 may be relevant to leukemia oncogenesis.27 SETBP1 is mutated at lower frequencies in unclassified MDS/MPN (10%) and CMML (4%), but no SETBP1 mutations are found in AML, acute lymphoblastic leukemia, chronic lymphocytic leukemia, or solid tumors.17 SETBP1 mutations in aCML were associated with higher white blood cell counts at diagnosis and poorer survival.17 Similarly, overall survival was significantly worse for CMML patients with SETBP1 mutations.28,29. SETBP1 overexpression is a novel leukemogenic mechanism that predicts adverse outcome in elderly patients with acute myeloid leukemia. CSF3R mutations arise in 2 classes, nonsense or frameshift mutations that truncate the cytoplasmic tail (truncation mutations) and point mutations in the extracellular domain (membrane proximal mutation), and some cases exhibit both classes of mutations on the same allele (compound mutations). Accepted: 10 June 2019. In addition to diagnostic and prognostic considerations, the pattern of tumor mutational architecture and acquisition may also have implications for therapeutic strategies and efficacy. Additional mutations in signaling pathway genes have been detected in CNL and aCML, with the most common events occurring in CBL, NRAS, KRAS, and JAK2, although at similar or lower frequency than is observed in other myeloid malignancies such as CMML or the classical myeloproliferative neoplasms.32,57,59 More recently, ETNK1 mutations have been detected in aCML60 with subsequent identification of similar mutations in CMML and systemic mastocytosis.61 A summary of the currently known mutated genes that co-occur in CNL and aCML is shown in Figure 3. CNL is characterized by more mature neutrophils and bands, whereas in aCML, there is an increase in both neutrophils and neutrophil precursors. Causes of reactive neutrophilia such as underlying infection or a tumor as well as other myeloid malignancies such as myelofibrosis, polycythemia vera, essential thrombocythemia, and myelodysplastic syndromes (MDSs) must be ruled out. Although it is highly unlikely that distinct clones with prevalent variants are frequently co-occurring in CNL/aCML patients, it is likely that some oligoclonality with heterogeneous mutation distribution is observed in some patients, as has frequently been reported in AML and other tumors. CNL may be the archetype of an MPN whose pathogenesis is predominantly characterized by mutations of CSF3R, whereas aCML may be more genetically heterogeneous. In the first model, a process of clonal hematopoiesis is originally associated with somatically acquired variants in genes that regulate epigenetic (eg, TET2, ASXL1) and/or splicing (eg, SRSF2, U2AF1) processes. Diagnostic tests include: 1. complete blood count (CBC) to measure the number and quality of white blood cells, re… Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm with a high prevalence (>80%) of mutations in the colony-stimulating factor 3 receptor (CSF3R). Kawashima, I., Kumagai, T., Suzuki, M. et al. Although splenic irradiation and splenectomy may provide transient palliation of symptomatic splenomegaly, the latter has been associated with anecdotal worsening of neutrophilic leukocytosis in CNL. Clinical, hematological and cytogenetic characteristics of atypical chronic myeloid leukemia. Percentages of CSF3R, SETBP1, and JAK2 V617F mutations in 29 patients with CNL or aCML are shown. After their initial discovery in aCML, SETBP1 mutations were also found in a variety of myeloid malignancies, including secondary AML, CMML, juvenile myelomonocytic leukemia, and MDS.37,47-49 In CMML, SETBP1 mutations seem to confer poor prognosis.50,51 Mutations in SETBP1 are therefore not specific to CNL. J.G. These patients receive long-term treatment with GCSF (the ligand for CSF3R) to combat their neutropenia and prevent the infections that are associated with low levels of neutrophils. Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm defined by persistent, predominantly mature neutrophil proliferation, … additionally serves on an Incyte advisory board. These mutations activate the receptor, leading to the proliferation of neutrophils that are a hallmark of CNL. In this regard, it is useful to consider the relative commonalities vs restriction of epigenetic, spliceosome, and signaling mutations for CNL and aCML vs other myeloid malignancies. Several of the genetic features associated with CNL and aCML have been associated with disease prognosis. Mutations in the spliceosome genes are seen at similar frequencies in other myeloid malignancies, although the apparent enrichment of the less common Q157 variant of U2AF1 in CSF3R-mutated CNL/aCML patients is intriguing.31,54,55. Chronic neutrophilic leukemia. Understanding the complete landscape and chronology of genomic events in CNL will help in the development of improved therapeutic strategies for this patient population. People with CNL have high levels of neutrophils (white blood cells that kill germs). Granulocyte colony-stimulating factor receptor signaling involves the formation of a three-component complex with Lyn and Syk protein-tyrosine kinases. Indeed, single-cell analyses from patients with polycythemia vera, essential thrombocythemia, or primary myelofibrosis revealed that some patients acquired epigenetic events such as TET2 mutations before acquisition of signaling lesions such as JAK2 V617F, but that there were also patients in whom the opposite was true.66 The specific model of clonal evolution into which a given patient’s disease falls may have important clinical implications in at least 3 areas. Chronic neutrophilic leukaemia: 14 new cases of an uncommon myeloproliferative disease. At a Glance. contributed to the writing of the manuscript. MPNs are blood cancers in which the bone marrow makes too many of one type of blood cell. Contribution: J.E.M. ‡Testing for JAK2 V617F, infrequently identified in CNL or atypical CML, should also be considered. It is thought that activation of the receptor through these mutations promotes the proliferation and differentiation of neutrophils, leading to the hyperproliferation of mature neutrophils that characterizes the CNL disease phenotype. Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice. A breakthrough in our understanding of the molecular basis of CNL came in 2013 with the discovery of colony-stimulating factor 3 receptor (CSF3R) mutations, also known as granulocyte colony–stimulating factor receptor (GCSFR), in the majority of patients (∼80%).12,14 Upon binding to its ligand (colony-stimulating factor 3 [CSF3] also known as granulocyte colony-stimulating factor [GCSF]), CSF3R acts to produce mature neutrophils in both steady state and demand granulopoiesis. Herein, we discuss the potential impact of these findings for the classification and treatment of these disorders. Jason Gotlib, Julia E. Maxson, Tracy I. George, Jeffrey W. Tyner; The new genetics of chronic neutrophilic leukemia and atypical CML: implications for diagnosis and treatment. © 2013 by The American Society of Hematology, Copyright ©2020 by American Society of Hematology, Histopathologic and clinical features of CNL and aCML, https://doi.org/10.1182/blood-2013-05-500959, granulocyte colony-stimulating factor receptors, philadelphia-negative myelogenous leukemia. The functional consequence of these truncations is altered and increased receptor activity conferring ligand hypersensitivity. Identification and characterization of SEB, a novel protein that binds to the acute undifferentiated leukemia-associated protein SET. Chronic neutrophilic leukaemia (CNL) is an extremely rare cancer originating in the bone marrow. Treatment options are limited for patients with CNL, with patients primarily receiving hydroxyurea and more rarely receiving interferon or a bone marrow transplant. CSF3R truncation mutations result in a loss of a portion of the cytoplasmic domain of the receptor, suggesting possible molecular mechanisms for receptor activation. Monocytosis and basophilia are not prominent (<2% peripheral blood basophils, <10% peripheral blood monocytes), and the leukocyte alkaline phosphatase level may be low, normal, or increased, therefore lacking diagnostic utility.4,8,9 A hypercellular bone marrow is observed with a myeloid hyperplasia and prominent granulocytic dysplasia, although multilineage dysplasia may be present. In both chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and chronic myeloid leukemia (CML), mature cell counts are closer to normal, resulting in less severe symptoms than in acute leukemias. Mutations in the degron motif therefore lead to SETBP1 overexpression, which can cause stabilization of its binding partner SET, and together they can inhibit the tumor suppressor PP2A. This case, although anecdotal, provides a strong rationale for the investigation of tyrosine kinase inhibitors (TKIs) in CNL and aCML patients. Truncated CSF3R may lack the di-leucine internalization motif, resulting in an increase in cell surface expression of the receptor.25 These truncated receptors may also lack the binding site for suppressor of cytokine signaling 3, which reduces trafficking of CSF3R to the lysosome. A 63-year-old female was incidentally found to have leukocytosis and referred to the hematology service for evaluation. In addition to mutations in the spliceosome complex, a number of events have also been observed in genes that regulate epigenetic processes in both acute and chronic myeloid malignancies. Your doctor will ask you about any symptoms you have and do a physical exam to check if your spleen or liver is enlarged. Taken together, the exclusivity of CSF3R mutations combined with the similarities of epigenetic and splicing mutations in CNL and aCML suggest that CSF3R mutations are acquired within a context and process of clonal hematopoiesis. Chronic neutrophilic leukemia (CNL) is a potentially aggressive myeloproliferative neoplasm, for which current WHO diagnostic criteria include leukocytosis of ≥ 25 x 10 9 /L of which ≥ 80% are neutrophils, with < 10% circulating neutrophil precursors with blasts rarely observed. Megakaryocytes are typically normal, but can include some small hypolobated megakaryocytes. Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia. BCR rearrangement-negative chronic myelogenous leukemia revisited. What's different about atypical CML and chronic neutrophilic leukemia? Peripheral blood flow cytometry was unremarkable without any evidence of lymphoproliferative disorder or myeloblasts. Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm that features a persistent neutrophilia in peripheral blood, myeloid hyperplasia in bone marrow, hepatosplenomegaly, and the absence of the Philadelphia chromosome or a BCR/ABL fusion gene. What Is Chronic Neutrophilic Leukemia? The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes. Chronic neutrophilic leukemia (CNL) is a rare, often aggressive myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis, bone marrow granulocyte hyperplasia, and frequent hepatosplenomegaly. SET binding protein 1 (SETBP1) mutations were discovered in 2012 in ∼25% of patients with aCML and were associated with significantly worse prognosis.39 Subsequent studies found that between 14% and 56% of patients with CNL also had SETBP1 mutations; the high degree of variability was likely a result of small cohort sizes.9,12,31,40 Among CNL patients, SETBP1 mutations are more likely to occur in those who harbor CSF3R mutations than in those who do not.9 SETBP1 was originally identified on the basis of its ability to bind SET oncoprotein through a yeast 2 hybrid screen.41 SET was previously implicated in leukemogenesis on the basis of the discovery that it can be part of a fusion protein with Nup214 in acute leukemia.42 SET was later found to be a negative regulator of the tumor suppressor protein phosphatase 2A (PP2A), which has many cellular roles, including inhibition of cellular proliferation.43 Overexpression of SETBP1 can increase levels of SET and inhibit PP2A.44 Interestingly, a subset of patients with AML have SETBP1 overexpression, which is associated with worse prognosis.44. Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: Results of a long-term survey. Mutations in SETBP1 associated with hematologic malignancies are largely identical to those found in patients with Schinzel-Giedion syndrome.39,45 The most prevalent SETBP1 mutations in myeloid malignancies are D868N and G870S. It will also be important to understand whether patients with early acquisition of CSF3R mutation may exhibit superior response compared with patients in whom CSF3R mutations are later-occurring events in the evolution of disease. These distinct mechanisms may contribute to the differential downstream signaling and drug sensitivity of truncation vs membrane proximal mutations. We apologize to investigators whose work was not included and referenced in this review due to space restrictions. The most common CSF3R mutation in CNL/aCML is the membrane proximal mutation: T618I. Truncation mutations in the cytoplasmic domain (gray) cause increased cell-surface expression of the receptor. and J.W.T. β-TrCP1 binding leads to formation of an E3 ligase complex to degrade SETBP1. AT-hook, DNA-binding motif that prefers AT-rich sequences; SKI, V-Ski avian sarcoma viral oncogene homolog. Recently, the World Health Organization guidelines have been updated to include CSF3R mutations as part of the diagnostic criteria for CNL. In contrast to the CSF3R T618I mutation, the truncation mutations alone do not cause leukemia in mouse models,29 but they can accelerate the development of disease in the presence of another genetic event driving leukemia.30 Consistent with the in vivo data, the CSF3R truncation mutations display slower cell transformation kinetics than the T618I mutation in cellular assays14 and require ligand for the activation of downstream signaling pathways.
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