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1.
Histopathology ; 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34637146

RESUMO

AIMS: It is unknown whether Epstein-Barr virus (EBV) infection can occur in high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit or triple-hit lymphoma (DHL/THL). METHODS AND RESULTS: Here we report 16 cases of EBV+ DHL/THL from screening 846 cases of DHL/THL and obtaining additional EBV+ cases through multi-institutional collaboration: 8 MYC/BCL2 DHL, 6 MYC/BCL6 DHL, and 2 THL. There were 8 men and 8 women with a median age of 65 years (range, 32-86). Two patients had a history of follicular lymphoma and one had AIDS. Nine of 14 patients had an International Prognostic Index of ≥3. Half of the cases showed high-grade/Burkitt-like morphology and the other half diffuse large B-cell lymphoma morphology. By immunohistochemistry, the lymphoma cells were positive for MYC (n=14/16), BCL2 (n=12/16), BCL6 (n=14/16), CD10 (n=13/16), and MUM1 (n=6/14). By Hans algorithm, 13 cases were classified as GCB and 3 as non-GCB. The lymphomas frequently showed an EBV latency type I with a median EBV-encoded small RNAs of 80% positive cells (range, 20-100%). After a median follow-up of 36.3 months (range, 2.0-41.6), 7 patients died with a median survival of 15.4 months (range, 3.4-47.3) after diagnosis of EBV+ DHL/THL. Five of 6 patients with MYC/BCL6 DHL were alive including 4 in complete remission. In contrast, only 4/10 patients with MYC/BCL2 DHL or THL were alive including 2 in complete remission. The median survival in patients with MYC/BCL6 DHL was unreached and was 21.6 months in patients with MYC/BCL2 DHL or THL. CONCLUSIONS: EBV infection in DHL/THL is rare (~1.5%). Cases of EBV+ DHL/THL are largely similar to their EBV-negative counterparts clinicopathologically. Our findings expand the spectrum of EBV+ B-cell lymphomas currently recognized in the WHO classification and suggest differences between EBV+ MYC/BCL2 and MYC/BCL6 DHL that may have therapeutic implications.

3.
FASEB J ; 35(9): e21789, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34383983

RESUMO

Normal pregnancy is essential for human reproduction. However, BaP (benzo(a)pyrene) and its metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) could cause dysfunctions of human trophoblast cells and might further induce miscarriage. Yet, the underlying mechanisms remain largely unknown. Herein, we identified a novel upregulated lnc-HZ04 and a novel downregulated miR-hz04 in villous tissues of unexplained recurrent miscarriage (RM) relative to those in healthy control tissues and also in BPDE-treated human trophoblast cells. Lnc-HZ04 directly and specifically bound with miR-hz04, diminished the reduction effects of miR-hz04 on IP3 R1 mRNA expression level and on IP3 R1 mRNA stability, and then activated the Ca2+ -mediated IP3 R1 /p-CaMKII/SGCB pathway, which further promoted trophoblast cell apoptosis. The miR-hz04 target site on lnc-HZ04 played crucial roles in these regulations. In normal trophoblast, relatively less lnc-HZ04 and more miR-hz04 suppressed this apoptosis pathway and gave normal pregnancy. After exposure to BPDE or in RM tissues, p53 was upregulated, which might promote p53-mediated lnc-HZ04 transcription. Relatively more lnc-HZ04 and less miR-hz04 activated this apoptosis pathway and might further induce miscarriage. BaP could also induce mice miscarriage by upregulating its corresponding murine apoptosis pathway. Therefore, BPDE-induced apoptosis of human trophoblast cells was associated with the occurrence of miscarriage. This work discovered the regulation roles of lnc-HZ04 and miR-hz04 and provided scientific and clinical understanding of the occurrence of unexplained miscarriage.


Assuntos
Aborto Habitual/genética , Apoptose/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Transdução de Sinais/genética , Trofoblastos/metabolismo , Regulação para Cima/genética , 7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido/farmacologia , Aborto Habitual/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Feminino , Humanos , Receptores de Inositol 1,4,5-Trifosfato/genética , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Sarcoglicanas/genética , Transdução de Sinais/efeitos dos fármacos , Trofoblastos/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
4.
Animals (Basel) ; 11(7)2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34359112

RESUMO

Genomic imprinting is the epigenetic mechanism of transcriptional regulation that involves differential DNA methylation modification. Comparative analysis of imprinted genes between species can help us to investigate the biological significance and regulatory mechanisms of genomic imprinting. MKRN3, MAGEL2 and NDN are three maternally imprinted genes identified in the human PWS/AS imprinted locus. This study aimed to assess the allelic expression of MKRN3, MAGEL2 and NDN and to examine the differentially methylated regions (DMRs) of bovine PWS/AS imprinted domains. An expressed single-nucleotide polymorphism (SNP)-based approach was used to investigate the allelic expression of MKRN3, MAGEL2 and NDN genes in bovine adult tissues and placenta. Consistent with the expression in humans and mice, we found that the MKRN3, MAGEL2 and NDN genes exhibit monoallelic expression in bovine somatic tissues and the paternal allele expressed in the bovine placenta. Three DMRs, PWS-IC, MKRN3 and NDN DMR, were identified in the bovine PWS/AS imprinted region by analysis of the DNA methylation status in bovine tissues using the bisulfite sequencing method and were located in the promoter and exon 1 of the SNRPN gene, NDN promoter and 5' untranslated region (5'UTR) of MKRN3 gene, respectively. The PWS-IC DMR is a primary DMR inherited from the male or female gamete, but NDN and MKRN3 DMR are secondary DMRs that occurred after fertilization by examining the methylation status in gametes.

5.
Int J Lab Hematol ; 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34431226
6.
Br J Haematol ; 194(3): 530-536, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34132393

RESUMO

COVID-19, caused by SARS-CoV-2, is a contagious life-threatening viral disease that has killed more than three million people worldwide to date. Attempts have been made to identify biomarker(s) to stratify disease severity and improve treatment and resource allocation. Patients with SARS-COV-2 infection manifest with a higher inflammatory response and platelet hyperreactivity; this raises the question of the role of thrombopoiesis in COVID-19 infection. Immature platelet fraction (IPF, %) and immature platelet counts (IPC, ×109 /l) can be used to assess thrombopoiesis. This study investigates whether the level of thrombopoiesis correlates with COVID-19 severity. A large cohort of 678 well-characterized COVID-19 patients was analyzed, including 658 (97%) hospitalized and 139 (21%) admitted to the intensive care unit (ICU). Elevated percentage IPF at presentation was predictive of length of hospitalization (P < 0·01) and ICU admission (P < 0·05). Additionally, percentage IPF at the peak was significantly higher among ICU patients than non-ICU patients (6·9 ± 5·1 vs 5·3 ± 8·4, P < 0·01) and among deceased patients than recovered patients (7·9 ± 6·3 vs 5·4 ± 7·8, P < 0·01). Furthermore, IPC at the peak was significantly higher among ICU patients than non-ICU patients (18·5 ± 16·2 vs. 13·2 ± 8·3, P < 0·05) and among patients on a ventilator than those not (22·1 ± 20·1 vs.13·4 ± 8·4, P < 0·05). Our study demonstrated that elevated initial and peak values of percentage IPF and IPC might serve as prognostic biomarkers for COVID-19 progression to severe conditions.


Assuntos
Plaquetas/patologia , COVID-19/patologia , Trombopoese , Idoso , Plaquetas/citologia , COVID-19/sangue , COVID-19/mortalidade , Feminino , Hospitalização , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença
7.
Am J Clin Pathol ; 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34160005

RESUMO

OBJECTIVES: New B-cell markers are needed for monitoring B lymphoblastic leukemia (B-ALL) in the era of immunotherapies directed against CD19 and CD22. The expression of leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) on hematogones in bone marrow (BM) and neoplastic B lymphoblasts has not yet been systematically investigated. METHODS: We assessed LILRB1 expression pattern on B cells in 19 control BMs and 22 B-ALL cases by flow cytometry. RESULTS: In all cases, mature B cells and hematogones exhibited a consistent pattern of LILRB1 expression with variable intensity over different stages of maturation, including a characteristic V-shaped pattern on hematogones. While neoplastic B lymphoblasts in all cases expressed LILRB1, the pattern of expression was distinctly abnormal relative to hematogones (loss of the dynamic pattern in all cases and abnormal expression levels in 83% of cases). CONCLUSIONS: LILRB1 is a novel diagnostic B-cell marker to aid in distinguishing neoplastic B lymphoblasts from hematogones.

8.
Ann Clin Lab Sci ; 51(2): 174-181, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33941556

RESUMO

The activation of the programmed cell death one (PD1)/PD1 ligand (PD-L1) immune checkpoint pathway is a mechanism of immune evasion characterized by the upregulation of PD-L1 expression by tumor cells and by the tumor microenvironment. This activation leads to the inhibition of PD1-positive T cells and to a decrease in the anti-tumor immune response. Plasmablastic lymphoma (PBL) is an aggressive type of large B-cell lymphoma with limited studies on the frequency of PD1 and PD-L1 expressions and their clinical impact. As PBL is associated with immune suppression in immunocompromised individuals, we hypothesize that the PD1/PD-L1 axis may be relevant in this type of lymphoma. Our study demonstrates a subset of PBL cases with a higher PD-L1 expression by tumor cells [nPD-L1high, in 4 of 21 (19%) cases] and by tumor microenvironment [macrophages/stromal cells, sPD-L1high, in 9 of 21 (43%) cases]. While nPD-L1 expression showed no significant correlation with PD1 expression on tumor-infiltrating lymphocytes, or other clinicopathological parameters, it positively correlated with sPD-L1 expression. Moreover, patients with nPD-L1high had a tendency towards a shorter overall survival (median 9.3 vs. 25.5 months in nPD-L1low patients). In conclusion, our study provides a rationale to identify, by immunohistochemistry, a subset of nPD-L1high patients who may benefit from clinical trials of PD1/PD-L1 checkpoint blockade. Further studies on large cohorts are needed to investigate prognostic and predictive biomarkers for the PD1/PD-L1 pathway in PBL patients.


Assuntos
Antígeno B7-H1/metabolismo , Linfoma Plasmablástico/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Adulto , Antígeno B7-H1/genética , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Linfócitos do Interstício Tumoral/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Linfoma Plasmablástico/genética , Linfoma Plasmablástico/fisiopatologia , Prognóstico , Receptor de Morte Celular Programada 1/genética , Células Estromais/metabolismo , Texas , Microambiente Tumoral/genética
9.
Leuk Res ; 106: 106584, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33933715

RESUMO

While dysregulation of MYC has been implicated in acute myeloid leukemia (AML), the impact of MYC protein expression in AML is less well understood. We investigated the correlation of MYC protein expression by immunohistochemistry (MYC-IHC) with MYC abnormalities and prognosis in adult de novo AML. MYC-IHC in bone marrow of patients with untreated AML (n = 58) was assessed and scored as MYClow (0-40 % of blasts) or MYChigh (> 40 % of blasts). This was correlated with MYC abnormalities by fluorescence in situ hybridization (FISH) and prognosis in the context of cytogenetic risk stratification. Residual myeloid disease at the end of induction was assessed by flow cytometry. MYClow and MYChigh were detected in 24 (41 %) and 34 cases (59 %), respectively. Extra copies of MYC were present in 12 % of cases and were not correlated with level of MYC-IHC. No cases had MYC translocation or amplification. Compared to MYClow patients, MYChigh patients had a shorter overall survival in all cytogenetic risk groups (68 vs. 21 months, p = 0.006) and in the intermediate risk group (61 vs. 21 months, p = 0.046). MYChigh patients had a tendency towards detected residual disease at the end of induction in all cytogenetic risk and intermediate risk groups. Regardless of the underlying mechanisms of MYC dysregulation, high level of MYC protein is expressed in the majority of AML and correlated to worse prognosis. Further studies on MYC dysregulation in leukemogenesis and therapy targeting MYC aberration are warranted.


Assuntos
Expressão Gênica , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Biomarcadores Tumorais , Análise Citogenética , Humanos , Imunofenotipagem , Leucemia Mieloide Aguda/mortalidade , Prognóstico , Reprodutibilidade dos Testes
10.
J Med Case Rep ; 15(1): 221, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33926575

RESUMO

BACKGROUND: Extranodal natural killer/T-cell lymphoma is a rare, aggressive non-Hodgkin lymphoma that is treated upfront mostly with L-asparaginase containing regimens. Relapsed extranodal natural killer/T-cell lymphoma is associated with a poor prognosis, and there is no established standard of care. CASE PRESENTATION: We report the case of a 72 year-old white male with a distant extranasal relapse of extranodal natural killer/T-cell lymphoma that has been managed successfully with a combination of radiation and immune checkpoint blockade with pembrolizumab. Pseudoprogression with new skin and bone lesions on positron emission tomography imaging was encountered during this Caucasian patient's immunotherapy and was successfully managed with supportive care and continuation of immune checkpoint blockade. CONCLUSIONS: The patient has been in complete clinical, radiologic, and molecular remission for close to 3 years and has not had any immune-related adverse effects. Pseudoprogression is a clinical challenge that can be encountered while patients are treated with immunotherapy, and astute clinical acumen is needed for accurate management. We believe this is the longest duration of response to immune checkpoint blockade in relapsed extranodal natural killer/T-cell lymphoma reported to date in literature. There is a strong biologic rationale in combining radiation with immunotherapy. The optimal timing, dose, and duration of radiation combined with immunotherapy in extranodal natural killer/T-cell lymphoma need to be prospectively evaluated.


Assuntos
Linfoma Extranodal de Células T-NK , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/uso terapêutico , Humanos , Inibidores de Checkpoint Imunológico , Células Matadoras Naturais , Linfoma Extranodal de Células T-NK/diagnóstico por imagem , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma Extranodal de Células T-NK/radioterapia , Masculino , Recidiva Local de Neoplasia/terapia
11.
Cell Biol Toxicol ; 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33864160

RESUMO

Increasing evidences have shown that pregnant women might miscarry after exposure with environmental BaP (benzo(a)pyrene). Additionally, BPDE (benzo(a)pyren-7,8-dihydrodiol-9,10-epoxide), the ultimate metabolite of BaP, could induce dysfunctions of human trophoblast cells. However, it is rarely correlated between miscarriage and trophoblast dysfunctions. Moreover, their underlying mechanisms are still largely unidentified. In this study, a novel lncRNA (long non-coding RNA), lnc-HZ08, was identified to be highly expressed in human recurrent miscarriage (RM) tissues and in BPDE-treated human trophoblast cells. Lnc-HZ08 acts as a RNA scaffold to interact with both PI3K and its ubiquitin ligase CBL (Cbl proto-oncogene), enhances their protein interactions, and promotes PI3K ubiquitin degradation. In RM tissues and BPDE-treated trophoblast cells, DNA methylation level in lnc-HZ08 promoter region was reduced, which promotes estrogen receptor 1 (ER)-mediated lnc-HZ08 transcription. Subsequently, this upregulated lnc-HZ08 downregulated PI3K level, suppressed PI3K/p-AKT/p-P21/CDK2 pathway, and thus weakened proliferation, migration, and invasion of human trophoblast cells, which further induces miscarriage. These results may provide novel scientific and clinical insights in the occurrence of unexplained miscarriage. A novel lncRNA (lnc-HZ08) regulates the functions of human trophoblast cells and affects miscarriage. Lnc-HZ08 promotes PI3K ubiquitin degradation by enhancing CBL and PI3K interactions, downregulates PI3K/p-AKT/p-P21/CDK2 pathway, and weakens proliferation, migration, and invasion of trophoblast cells. BPDE exposure reduces the DNA methylation level in lnc-HZ08 promoter region and promotes estrogen receptor 1 (ER)-mediated lnc-HZ08 transcription. The suppressed PI3K/p-AKT/p-P21/CDK2 pathway regulated by increased lnc-HZ08 is associated with miscarriage. These results provide novel insights in the occurrence of unexplained miscarriage. Graphical Headlights • Lnc-HZ08 downregulates PI3K/p-AKT/p-P21/CDK2 pathway to suppress proliferation, migration, and invasion of human trophoblast cells, and affects miscarriage. • Lnc-HZ08 acts as a RNA scaffold to enhance the protein interaction of PI3K and its ubiquitin ligase CBL, which increases PI3K ubiquitination and degradation. • Lnc-HZ08 transcription is associated with DNA methylation on its promoter region and transcription factor ER.

13.
Sci Total Environ ; 776: 145950, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33647641

RESUMO

Environmental BaP (benzo(a)pyrene) and its metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) inhibit proliferation of human villous trophoblast cells, which might further induce recurrent miscarriage (RM). However, the underlying mechanisms remain largely unknown. In this work, we identified a novel lncRNA HZ01 (lnc-HZ01) that is up-regulated in both RM tissues and BPDE-exposed trophoblast cells. Lnc-HZ01 inhibits trophoblast cell proliferation and induces miscarriage. Mechanistically, lnc-HZ01 promotes MXD1 mRNA transcription by up-regulating its transcription factor c-JUN and also enhances MXD1 protein stability by up-regulating its deubiquitin enzyme USP36. Reversely, MXD1 up-regulates lnc-HZ01 level by enhancing its RNA stability due to the increased level of m6A RNA methylation on lnc-HZ01, the first example that m6A modification regulates trophoblast cell functions. Thus, lnc-HZ01 and MXD1 comprise a positive self-feedback loop, which is up-regulated in both RM tissues and BPDE-exposed trophoblast cells. Once this loop is activated by BaP or BPDE exposure, both pathways in this loop would be up-regulated, promote EIF4E transcription, inhibit trophoblast cell proliferation, and further induce miscarriage. This work provides new clinical and scientific understanding in unexplained miscarriage.


Assuntos
Aborto Espontâneo , RNA Longo não Codificante , 7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Proliferação de Células , Retroalimentação , Feminino , Humanos , Metilação , Gravidez , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas Repressoras/metabolismo , Trofoblastos/metabolismo
14.
Cancers (Basel) ; 13(4)2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33669719

RESUMO

Primary effusion lymphoma (PEL) is a rare type of large B-cell lymphoma associated with human herpesvirus 8 (HHV8) infection. Patients with PEL usually present with an effusion, but occasionally with an extracavitary mass. In this study, we reported a cohort of 70 patients with PEL: 67 men and 3 women with a median age of 46 years (range 26-91). Of these, 56 (80%) patients had human immunodeficiency virus (HIV) infection, eight were HIV-negative, and six had unknown HIV status. Nineteen (27%) patients had Kaposi sarcoma. Thirty-five (50%) patients presented with effusion only, 27 (39%) had an extracavitary mass or masses only, and eight (11%) had both effusion and extracavitary disease. The lymphoma cells showed plasmablastic, immunoblastic, or anaplastic morphology. All 70 (100%) cases were positive for HHV8. Compared with effusion-only PEL, patients with extracavitary-only PEL were younger (median age, 42 vs. 52 years, p = 0.001), more likely to be HIV-positive (88.9% vs. 68.6%, p = 0.06) and EBV-positive (76.9% vs. 51.9%, p = 0.06), and less often positive for CD45 (69.2% vs. 96.2%, p = 0.01), EMA (26.7% vs. 100%, p = 0.0005), and CD30 (60% vs. 81.5%, p = 0.09). Of 52 (50%) patients with clinical follow-up, 26 died after a median follow-up time of 40.0 months (range 0-96), and the median overall survival was 42.5 months. The median OS for patients with effusion-only and with extracavitary-only PEL were 30.0 and 37.9 months, respectively (p = 0.34), and patients with extracavitary-only PEL had a lower mortality rate at the time of last follow-up (35% vs. 61.5%, p = 0.07). The median OS for HIV-positive and HIV-negative patients were 42.5 and 6.8 months, respectively (p = 0.57), and they had a similar mortality rate of 50% at last follow-up. In conclusion, patients presenting with effusion-only versus extracavitary-only disease are associated with different clinicopathologic features. PEL is an aggressive lymphoma with a poor prognosis, regardless of extracavitary presentation or HIV status.

16.
J Pediatr Hematol Oncol ; 43(3): e388-e394, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32925408

RESUMO

BACKGROUND: Ewing sarcoma breakpoint region 1 gene (EWSR1) rearrangements are largely associated with the Ewing sarcoma family of tumors. OBSERVATIONS: We report the first case of infantile, mixed phenotype acute leukemia, B/myeloid (bilineal and biphenotypic [B-lymphoid and B-lymphoid/myeloid]), with a t(2;22)(q35;q12). The EWSR1-fifth Ewing variant gene fusion and nonsense mutation in STAG2 were detected by next-generation sequencing and markedly high expression of fifth Ewing sarcoma variant mRNA detected by quantitative reverse transcription polymerase chain reaction. The patient was treated with a combined myeloid/lymphoid leukemia regimen followed by allogeneic stem cell transplant and was in complete remission at 3.8-year follow-up. CONCLUSIONS: Our case study underscores the importance of a comprehensive evaluation of acute leukemia and provides insights into the phenotype of EWSR1 rearranged neoplasms in the context of partner genes and cell type.


Assuntos
Proteínas de Ligação a DNA/genética , Leucemia Aguda Bifenotípica/genética , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/genética , Proteína EWS de Ligação a RNA/genética , Fatores de Transcrição/genética , Proteínas de Ciclo Celular/genética , Códon sem Sentido , Feminino , Humanos , Lactente , Translocação Genética
17.
Leuk Res ; 100: 106480, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33285315

RESUMO

Central nervous system (CNS) involvement in patients with acute myeloid leukemia (AML) varies, ranging from 0.6%-46%. Leukocyte immunoglobulin-like receptor B4 (LILRB4) has been shown to be critical in orchestration of infiltration of AML cells into the CNS in animal models, however it is unknown if an association exists between LILRB4 and CNS involvement (CNS+) in human patients with AML. LILRB4 was measured by flow cytometry in a heterogeneous population of fifty-six AML patients. Patients were then followed clinically for the development of CNS + . LILRB4 was positive in 91 % of patients with CNS + compared to 38 % without CNS involvement (p < 0.002). In logistic analysis: age, BMI, serum albumin and positive LILRB4 were predictive for CNS+ [OR, 95 % CI, p-value]: 0.95, 0.92-0.99, p < 0.01; 0.85, 0.73-0.998, p < 0.05; 0.23, 0.066-0.78, p < 0.02; 16.46, 1.93-140.2, p < 0.02, respectively. This finding of the association of LILRB4 with CNS + in combination with earlier findings suggests that LILRB4 has a mechanistic role in infiltration of the CNS and may provide insight into the pathogenesis of AML seeding the CNS. Moreover, this proof of concept and the findings in the present study may lead to the development of innovative and novel therapies to improve the lives of patients with AML.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/patologia , Leucemia Mieloide Aguda/patologia , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Nervoso Central/etiologia , Neoplasias do Sistema Nervoso Central/metabolismo , Criança , Pré-Escolar , Citarabina/administração & dosagem , Feminino , Seguimentos , Humanos , Idarubicina/administração & dosagem , Lactente , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Adulto Jovem
18.
Artigo em Inglês | MEDLINE | ID: mdl-32918786

RESUMO

BACKGROUND: Acute myeloid leukemia (AML) with monocytic differentiation (M-AML) remains a diagnostic challenge largely due to lack of sensitive and specific markers for immature monocytes. The immunoglobulin-like inhibitory receptors, LILRB1 and LILRB4, are expressed on monocytes but have not yet been systematically evaluated in the clinical setting. METHODS: We evaluated the diagnostic performance of LILRB1 and LILRB4 as monocytic markers for both immature and mature monocytes in comparison to other myelomonocytic markers including CD14, CD15, CD33, CD36, and CD64 in eight cases of control bone marrow (BM, 5) and peripheral blood (PB, 3), 64 cases of (M-AML), and 57 cases of AML without monocytic differentiation (NM-AML) by flow cytometric immunophenotyping. RESULTS: In control BM, LILRB1 and LILRB4 were consistently expressed on monocytes at all stages of maturation, from CD34+ /CD14- monocytic precursors to CD14-/dim+ maturing and CD14+ mature monocytes. In M-AML, LILRB1 and LILRB4 were consistently expressed on monocytes, regardless of the degree of maturity, from CD14-/dim+ monoblasts/promonocytes to CD14+ mature monocytes but were not expressed on myeloblasts. The diagnostic performances as a monocytic marker assessed by sensitivity/specificity were 100%/100% for LILRB1/LILRB4, 100%/82% for CD11b, 80%/100% for CD14, 100%/81% for CD64, 100%/58% for CD15/CD33, and 89%/97% for CD36/CD64. CONCLUSION: The co-expression of LILRB1/LILRB4 outperformed other myelomonocytic markers as a highly sensitive and specific marker for monocytes at all stages of maturation and could reliably distinguish M-AML from NM-AML. LILRB4 additionally represents a novel therapeutic target for treating M-AML.

19.
Am J Clin Pathol ; 154(6): 816-827, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-32880627

RESUMO

OBJECTIVES: Autologous stem cell transplant with lenalidomide maintenance therapy has greatly improved the relapse-free and overall survival rates of patients with multiple myeloma but also has been associated with an increased risk of secondary B-lymphoblastic leukemia/lymphoma (B-ALL). METHODS: We report a comprehensive review of the clinicopathologic features of 2 patients with multiple myeloma who developed secondary B-ALL during lenalidomide maintenance. RESULTS: Our observations showed that the disease may initially present with subtle clinical, morphologic, and flow-cytometric findings. The flow cytometry findings in such cases may initially mimic an expansion of hematogones with minimal immunophenotypic variation. Both patients achieved complete remission of secondary B-ALL after standard chemotherapy; however, one patient continues to have minimal residual disease, and the other experienced relapse. Next-generation sequencing of the relapse specimen showed numerous, complex abnormalities, suggesting clonal evolution. CONCLUSIONS: Our findings suggest the need for increased awareness and further study of this unique form of secondary B-ALL.


Assuntos
Fatores Imunológicos , Lenalidomida/efeitos adversos , Mieloma Múltiplo/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/induzido quimicamente , Adulto , Antineoplásicos/uso terapêutico , Medula Óssea/química , Medula Óssea/patologia , Análise Citogenética , Evolução Fatal , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lenalidomida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Recidiva , Indução de Remissão , Transplante de Células-Tronco
20.
J Immunother Cancer ; 8(2)2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32771992

RESUMO

BACKGROUND: Current immune checkpoint blockade strategies have been successful in treating certain types of solid cancer. However, checkpoint blockade monotherapies have not been successful against most hematological malignancies including multiple myeloma and leukemia. There is an urgent need to identify new targets for development of cancer immunotherapy. LILRB1, an immunoreceptor tyrosine-based inhibitory motif-containing receptor, is widely expressed on human immune cells, including B cells, monocytes and macrophages, dendritic cells and subsets of natural killer (NK) cells and T cells. The ligands of LILRB1, such as major histocompatibility complex (MHC) class I molecules, activate LILRB1 and transduce a suppressive signal, which inhibits the immune responses. However, it is not clear whether LILRB1 blockade can be effectively used for cancer treatment. METHODS: First, we measured the LILRB1 expression on NK cells from cancer patients to determine whether LILRB1 upregulated on NK cells from patients with cancer, compared with NK cells from healthy donors. Then, we developed specific antagonistic anti-LILRB1 monoclonal antibodies and studied the effects of LILRB1 blockade on the antitumor immune function of NK cells, especially in multiple myeloma models, in vitro and in vivo xenograft model using non-obese diabetic (NOD)-SCID interleukin-2Rγ-null mice. RESULTS: We demonstrate that percentage of LILRB1+ NK cells is significantly higher in patients with persistent multiple myeloma after treatment than that in healthy donors. Further, the percentage of LILRB1+ NK cells is also significantly higher in patients with late-stage prostate cancer than that in healthy donors. Significantly, we showed that LILRB1 blockade by our antagonistic LILRB1 antibody increased the tumoricidal activity of NK cells against several types of cancer cells, including multiple myeloma, leukemia, lymphoma and solid tumors, in vitro and in vivo. CONCLUSIONS: Our results indicate that blocking LILRB1 signaling on immune effector cells such as NK cells may represent a novel strategy for the development of anticancer immunotherapy.

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