RESUMO
We present 2 diagnostically challenging cases of pediatric/adolescent relapsed/refractory aggressive mature B-cell non-Hodgkin lymphoma (B-NHL) within the spectrum of Burkitt lymphoma and diffuse large B-cell lymphoma and illustrate the different therapeutic regimens that are employed for pediatric and adult cancer centers. Both cases displayed varying-sized lymphoma cells with occasional single prominent nucleoli and heterogeneous BCL2 expression. Cytogenetics revealed complex karyotypes with t(8:14)(q24.2;q32) and IGH::MYC rearrangement by FISH. Next generation sequencing revealed deleterious TP53 and MYC mutations. We concluded that both could be diagnosed as "DLBCL-NOS with MYC rearrangement" using the current pathologic classifications, 2022 International Consensus Classification (ICC) and World Health Organization Classifications of Haematolymphoid Tumors (WHO-HAEM5). This report illustrates diagnostic challenges and treatment dilemmas that may be encountered, particularly for adolescent and young adults (AYA).
Assuntos
Linfoma de Burkitt , Linfoma Difuso de Grandes Células B , Proteínas Proto-Oncogênicas c-bcl-2 , Translocação Genética , Humanos , Linfoma de Burkitt/genética , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/patologia , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/terapia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Adolescente , Masculino , Criança , Feminino , Diagnóstico Diferencial , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Cromossomos Humanos Par 14/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/genética , Cromossomos Humanos Par 8/genéticaRESUMO
Programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are immunomodulatory molecules overexpressed in lymphomas and are promising immunotherapy targets for hematologic malignancies. However, studies of PD-1/PD-L1 overexpression and their clinical significance in aggressive pediatric non-Hodgkin lymphomas (NHL) are limited. We assessed PD-1/PD-L1 overexpression using immunohistochemistry in 68 aggressive pediatric NHL: ALK-positive anaplastic large cell lymphoma (ALK+ ALCL, n=8), Burkitt lymphoma (BL, n=27), and large B-cell lymphoma (LBCL) de novo LBCL, n=22 and diffuse LBCL arising as monomorphic post-transplant lymphoproliferative disorder [PTLD-DLBCL], n=11. In LBCL, correlations between PD-L1 overexpression and Epstein-Barr virus (EBV) status, cell of origin, stage, nodal status, overall survival (OS), and event-free survival (EFS) were examined. The genetic mechanisms of PD-L1 overexpression were investigated using targeted next-generation sequencing (NGS) and cytogenetic data. All ALK+ ALCL samples, 50.0% of de novo LBCL (11/22), 72.7% of PTLD-DLBCL (8/11), and no BL overexpressed PD-L1. Overexpressed PD-L1 correlated with EBV positivity (P=0.033) in LBCL and lower EFS in de novo LBCL (P=0.017). NGS of select LBCL revealed distinct somatic mutations and an ultra-hypermutated PTLD-DLBCL. Most cases with 9p24.1 copy gains overexpressed PD-L1 although some cases had no discernible genetic drivers of PD-L1 overexpression. Overexpressed PD-L1 is common in pediatric LBCL, associated with EBV positivity and 9p24.1 gains, and may have prognostic significance in de novo LBCL. Furthermore, diverse molecular mechanisms for PD-L1 overexpression in aggressive pediatric NHL can occur. Thus, additional studies exploring the therapeutic and prognostic significance and molecular mechanisms of PD-L1 overexpression in aggressive pediatric NHL are warranted.
Assuntos
Infecções por Vírus Epstein-Barr , Linfoma Difuso de Grandes Células B , Linfoma Anaplásico de Células Grandes , Apoptose , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Criança , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4 , Humanos , Ligantes , Linfoma Difuso de Grandes Células B/genética , Receptor de Morte Celular Programada 1/metabolismo , Receptores Proteína Tirosina QuinasesRESUMO
Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth disorder caused by germline heterozygous mutations in the DNA methyltransferase DNMT3A. DNMT3A is a critical regulator of hematopoietic stem cell (HSC) differentiation and somatic DNMT3A mutations are frequent in hematologic malignancies and clonal hematopoiesis. Yet, the impact of constitutive DNMT3A mutation on hematopoiesis in TBRS is undefined. In order to establish how constitutive mutation of DNMT3A impacts blood development in TBRS we gathered clinical data and analyzed blood parameters in 18 individuals with TBRS. We also determined the distribution of major peripheral blood cell lineages by flow cytometric analyses. Our analyses revealed non-anemic macrocytosis, a relative decrease in lymphocytes and increase in neutrophils in TBRS individuals compared to unaffected controls. We were able to recapitulate these hematologic phenotypes in multiple murine models of TBRS and identified rare hematological and non-hematological malignancies associated with constitutive Dnmt3a mutation. We further show that loss of DNMT3A in TBRS is associated with an altered DNA methylation landscape in hematopoietic cells affecting regions critical to stem cell function and tumorigenesis. Overall, our data identify key hematopoietic effects driven by DNMT3A mutation with clinical implications for individuals with TBRS and DNMT3A-associated clonal hematopoiesis or malignancies.
Assuntos
DNA (Citosina-5-)-Metiltransferases , Deficiência Intelectual , Animais , DNA (Citosina-5-)-Metiltransferases/genética , DNA Metiltransferase 3A , Células Germinativas/patologia , Hematopoese/genética , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , CamundongosRESUMO
A 10-year-old female with a several-year history of pityriasis lichenoides (PL) presented with a new, asymptomatic, large, and necrotic ulcer of her right upper arm. Skin biopsy was consistent with lymphomatoid papulosis (LyP) Type D, a recently recognized subtype of LyP that is distinguished histologically by marked epidermotropism and a perivascular infiltrate of medium-sized pleomorphic lymphocytes with a cytotoxic phenotype (CD3+, CD8+). This is only the sixth reported case of LyP Type D in a child, and while the prognosis in children appears favorable, with no reports of progression to lymphoma to date, more experience in children with longer-term follow-up is needed. Our case highlights both the challenging clinical diagnosis, since in our patient the longstanding clinical presentation was indistinguishable from PL, as well as histopathologic diagnosis, which required expert opinion and consensus.
Assuntos
Papulose Linfomatoide , Pitiríase Liquenoide , Neoplasias Cutâneas , Feminino , Criança , Humanos , Papulose Linfomatoide/diagnóstico , Pitiríase Liquenoide/diagnóstico , Pele/patologia , Biópsia , Neoplasias Cutâneas/patologiaRESUMO
Rubinstein-Taybi syndrome (RSTS) is a rare disorder characterized by developmental delay, short stature, dysmorphic facies and skeletal abnormalities. RSTS has been linked to a variety of malignant and benign tumors, but the frequency and characteristics of RSTS-related neoplasms remain unclear. We describe a unique case of near haploid B-cell lymphoblastic leukemia (B-ALL) in a 6-year-old girl with RSTS who harbors a likely pathogenic variant in CREBBP. Somatic CREBBP variants are enriched in some subsets of ALL; however, germline variants have not been previously described in childhood leukemia and may represent an underrecognized predisposition to malignancy. Our patient's disease responded poorly to conventional chemotherapy and relapsed following a complete remission achieved with CD19 CAR T cell therapy. We propose that the constitutional CREBBP variant may have played a significant role in the leukemia's resistance to chemotherapy and this patient's poor response to therapy.
Assuntos
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras , Síndrome de Rubinstein-Taybi , Proteína de Ligação a CREB/genética , Criança , Aberrações Cromossômicas , Feminino , Genótipo , Haploidia , Humanos , Mutação , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/patologiaRESUMO
Autologous T cells targeting Epstein-Barr virus (EBV) latent membrane proteins (LMPs) have shown safety and efficacy in the treatment of patients with type 2 latency EBV-associated lymphomas for whom standard therapies have failed, including high-dose chemotherapy followed by autologous stem-cell rescue. However, the safety and efficacy of allogeneic donor-derived LMP-specific T cells (LMP-Ts) have not been established for patients who have undergone allogeneic hematopoietic stem-cell transplantation (HSCT). Therefore, we evaluated the safety and efficacy of donor-derived LMP-Ts in 26 patients who had undergone allogeneic HSCT for EBV-associated natural killer/T-cell or B-cell lymphomas. Seven patients received LMP-Ts as therapy for active disease, and 19 were treated with adjuvant therapy for high-risk disease. There were no immediate infusion-related toxicities, and only 1 dose-limiting toxicity potentially related to T-cell infusion was seen. The 2-year overall survival (OS) was 68%. Additionally, patients who received T-cell therapy while in complete remission after allogeneic HSCT had a 78% OS at 2 years. Patients treated for B-cell disease (n = 10) had a 2-year OS of 80%. Patients with T-cell disease had a 2-year OS of 60%, which suggests an improvement compared with published posttransplantation 2-year OS rates of 30% to 50%. Hence, this study shows that donor-derived LMP-Ts are a safe and effective therapy to prevent relapse after transplantation in patients with B cell- or T cell-derived EBV-associated lymphoma or lymphoproliferative disorder and supports the infusion of LMP-Ts as adjuvant therapy to improve outcomes in the posttransplantation setting. These trials were registered at www.clinicaltrials.gov as #NCT00062868 and #NCT01956084.
Assuntos
Infecções por Vírus Epstein-Barr/complicações , Transplante de Células-Tronco Hematopoéticas/métodos , Herpesvirus Humano 4/imunologia , Linfoma de Células B/terapia , Linfoma de Células T/terapia , Recidiva Local de Neoplasia/prevenção & controle , Linfócitos T/transplante , Adolescente , Adulto , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/imunologia , Feminino , Herpesvirus Humano 4/isolamento & purificação , Humanos , Linfoma de Células B/imunologia , Linfoma de Células B/virologia , Linfoma de Células T/imunologia , Linfoma de Células T/virologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Linfócitos T/imunologia , Transplante Homólogo/métodos , Resultado do Tratamento , Proteínas da Matriz Viral/imunologia , Adulto JovemRESUMO
Myeloid sarcoma (MS) is a neoplastic condition composed of immature myeloid cells involving an extramedullary site. We investigated underlying chromosomal and molecular alterations to assess potential molecular markers of prognosis and outcome in this rare pediatric disease. We conducted a retrospective review of clinicopathologic and cytogenetic data from 33 pediatric patients with MS (ages 1 month-18 years) at our institution over a 32 year period (1984-2016). Tissue-based cancer microarray and targeted next-generation sequencing analysis were performed on six cases. The median age at diagnosis was 2.8 years with a male-to-female ratio of 2.6:1. MS is commonly presented with concomitant marrow involvement (n = 12, 36.4%) or as a recurrence of acute myeloid leukemia (AML; n = 14, 42.4%). The skin (n = 18, 54.5%) and soft tissue (n = 9, 27.3%) were the most common sites of involvement. Twenty-one of 25 samples (84.0%) harbored chromosomal aberrations; KMT2A alterations (n = 10, 40.0%) or complex cytogenetics (n = 7, 28.0%) were most frequent. Mutations in RAS, tyrosine kinase, cell signaling, and chromatin remodeling genes were detected. When compared to pediatric patients with AML without extramedullary involvement (EMI), inferior overall survival (OS) was observed (18.8 months vs. 89.3 months, p = .008). Pediatric patients with MS with non-favorable cytogenetics [abnormalities other than t(8;21), inv(16)/t(16;16), or t(15;17)] had a significantly lower OS compared to patients with AML with non-favorable cytogenetics and no extramedullary involvement (8.0 months vs. 28.1 months, p < .001). Pediatric MS is a rare disease with diverse clinical presentations. Non-favorable cytogenetics may be a poor prognostic marker for pediatric patients with MS and molecular diagnostics can assist with risk stratification and identify potentially actionable targets.
Assuntos
Sarcoma Mieloide , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , MasculinoRESUMO
Neutropenia in pediatric patients can be due to a variety of disorders. We describe two patients who underwent extensive evaluation over many years for arthralgias and moderate neutropenia of unclear etiology. Genetic testing identified a pathogenic variant in PSTPIP1 (proline-serine-threonine phosphatase-interacting protein 1) in both patients. Markedly elevated inflammatory markers and zinc levels confirmed the rare diagnosis of PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome, tailoring treatment. Neutropenia is common in patients with PAMI syndrome. Unique mutations seen in PAMI syndrome may account for the specific phenotypic features of this disorder.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Artralgia/patologia , Proteínas do Citoesqueleto/genética , Inflamação/complicações , Erros Inatos do Metabolismo dos Metais/complicações , Mutação , Neutropenia/patologia , Artralgia/etiologia , Artralgia/genética , Criança , Feminino , Humanos , Neutropenia/etiologia , Neutropenia/genética , Fenótipo , Prognóstico , SíndromeRESUMO
BACKGROUND: Fanconi anemia is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Currently, no interventions to prevent or delay the formation of solid tumors are available. PROCEDURE: Two of the most important hallmarks of Fanconi anemia are inflammation and oxidative stress. In this study, we administrated the antioxidant atorvastatin and the anti-inflammatory drug celecoxib to cohorts of Fancd2-/- /Trp53+/- mice, a model of Fanconi anemia. Treatment started at weaning and continued until the mice developed a palpable mass or suffered from >20% weight loss. Tumor samples and selected tissues were subjected to histopathological examination. χ2 test was performed to analyze tumor incidence, and Kaplan-Meier survival curves were evaluated with log-rank test. In addition, a small cohort of mice was monitored for the safety of the drugs. RESULTS: The combined oral administration of both drugs significantly delayed tumor onset in Fancd2-/- /Trp53+/- mice. Specifically, the treatment delayed the onset of ovarian tumors in Fancd2-/- /Trp53+/- mice and increased the mean ovarian tumor-free survival time by 17%, whereas this combinatorial drug regimen did not have a significant effect on other tumor types. In addition, no detrimental effects on hematopoiesis from the drug treatment were observed during a 12-month safety monitoring. CONCLUSIONS: The data presented here suggest that a combination of atorvastatin and celecoxib may be a good candidate for chemoprevention in Fanconi anemia.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Modelos Animais de Doenças , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/fisiologia , Anemia de Fanconi/tratamento farmacológico , Proteína Supressora de Tumor p53/fisiologia , Animais , Atorvastatina/administração & dosagem , Celecoxib/administração & dosagem , Anemia de Fanconi/patologia , Feminino , Masculino , Camundongos , Camundongos Knockout , Taxa de SobrevidaRESUMO
Juvenile myelomonocytic leukemia (JMML) has a poor prognosis in general, with hematopoietic stem cell transplant (HSCT) remaining the standard of care for cure. The hypomethylating agent, azacitidine, has been used as a bridging therapy to transplant. However, no patients have been treated with azacitidine without an HSCT post azacitidine. We report on an infant with JMML with somatic KRAS G12A mutation and monosomy 7 who achieved sustained remission following azacitidine monotherapy. He also developed an aberrant B-lymphoblast population which declined with similar kinetics as his JMML-associated abnormalities, suggesting that a B-lymphoblast population in JMML does not always progress to acute leukemia.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Leucemia Mielomonocítica Juvenil/tratamento farmacológico , Células Precursoras de Linfócitos B/patologia , Deleção Cromossômica , Cromossomos Humanos Par 7 , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/patologia , Masculino , Indução de RemissãoRESUMO
BACKGROUND: Systemic forms of EBV-associated T-cell lymphoproliferative disorders of childhood (S-EBV-T-LPD) comprise three major forms: EBV-positive hemophagocytic lymphohistiocytosis (EBV-HLH), systemic EBV-positive T-cell lymphoma (S-EBV-TCL), and systemic chronic active EBV infection (S-CAEBV). These disorders occur rarely in children in Western countries. Here, we described eight children of such entities. DESIGN: Eight cases (six clinical and two autopsy) with S-EBV-T-LPD of childhood were retrospectively identified from 1990 to 2015. Clinicopathologic parameters including histomorphology, immunophenotype, EBV studies, and T-cell receptor gene rearrangement studies were recorded. RESULTS: Patients include five females and three males of Hispanic, Asian, and Caucasian origins with an age range of 14 months to 9 years. Fever, hepatosplenomegaly, cytopenias, abnormal EBV serologies, and very high EBV viral loads were common findings. Histologic findings showed EBV+ T-cell infiltrates with variable degrees of architectural distortion and cytologic atypia ranging from no to mild cytologic atypia to overt lymphoma and tissue hemophagocytosis. All showed aberrant CD4+ or CD8+ T cells with dim to absent CD5, CD7, and CD3, and bright CD2 and CD45 by flow cytometry or loss of CD5 by immunohistochemistry. TCR gene rearrangement studies showed monoclonal rearrangements in all clinical cases (6/6). Outcomes were poor with treatment consisting of chemotherapy per the HLH-94 or HLH-2004 protocols with or without bone marrow transplant. CONCLUSION: In this large pediatric clinicopathologic study of S-EBV-T-LPD of childhood in the United States, EBV-HLH, S-EBV-TCL, and S-CAEBV show many overlapping features. Diagnosis is challenging, and overall outcome is poor using current HLH-directed therapies.
Assuntos
Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4/isolamento & purificação , Linfoma de Células T/patologia , Transtornos Linfoproliferativos/patologia , Linfócitos T/patologia , Atenção Terciária à Saúde/estatística & dados numéricos , Medula Óssea/patologia , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Feminino , Seguimentos , Humanos , Lactente , Fígado/patologia , Linfonodos/patologia , Linfoma de Células T/classificação , Linfoma de Células T/etiologia , Transtornos Linfoproliferativos/classificação , Transtornos Linfoproliferativos/etiologia , Masculino , Prognóstico , Estudos RetrospectivosRESUMO
Primary T-cell acute lymphoblastic leukemia (T-ALL) cells require stromal-derived signals to survive. Although many studies have identified cell-intrinsic alterations in signaling pathways that promote T-ALL growth, the identity of endogenous stromal cells and their associated signals in the tumor microenvironment that support T-ALL remains unknown. By examining the thymic tumor microenvironments in multiple murine T-ALL models and primary patient samples, we discovered the emergence of prominent epithelial-free regions, enriched for proliferating tumor cells and dendritic cells (DCs). Systematic evaluation of the functional capacity of tumor-associated stromal cells revealed that myeloid cells, primarily DCs, are necessary and sufficient to support T-ALL survival ex vivo. DCs support T-ALL growth both in primary thymic tumors and at secondary tumor sites. To identify a molecular mechanism by which DCs support T-ALL growth, we first performed gene expression profiling, which revealed up-regulation of platelet-derived growth factor receptor beta (Pdgfrb) and insulin-like growth factor I receptor (Igf1r) on T-ALL cells, with concomitant expression of their ligands by tumor-associated DCs. Both Pdgfrb and Igf1r were activated in ex vivo T-ALL cells, and coculture with tumor-associated, but not normal thymic DCs, sustained IGF1R activation. Furthermore, IGF1R signaling was necessary for DC-mediated T-ALL survival. Collectively, these studies provide the first evidence that endogenous tumor-associated DCs supply signals driving T-ALL growth, and implicate tumor-associated DCs and their mitogenic signals as auspicious therapeutic targets.
Assuntos
Células Dendríticas/imunologia , Proteínas de Neoplasias/imunologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/imunologia , Receptores de Somatomedina/imunologia , Transdução de Sinais/imunologia , Microambiente Tumoral/imunologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Células Dendríticas/patologia , Feminino , Humanos , Masculino , Camundongos , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Receptor IGF Tipo 1 , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/imunologia , Receptores de Somatomedina/genética , Transdução de Sinais/genética , Microambiente Tumoral/genéticaRESUMO
Fanconi anemia (FA) is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Bone marrow transplantation is currently the only curative therapy for the hematopoietic complications of this disorder. However, long-term morbidity and mortality remain very high, and new therapeutics are badly needed. Here we show that the widely used diabetes drug metformin improves hematopoiesis and delays tumor formation in Fancd2-/- mice. Metformin is the first compound reported to improve both of these FA phenotypes. Importantly, the beneficial effects are specific to FA mice and are not seen in the wild-type controls. In this preclinical model of FA, metformin outperformed the current standard of care, oxymetholone, by improving peripheral blood counts in Fancd2-/- mice significantly faster. Metformin increased the size of the hematopoietic stem cell compartment and enhanced quiescence in hematopoietic stem and progenitor cells. In tumor-prone Fancd2-/-Trp53+/- mice, metformin delayed the onset of tumors and significantly extended the tumor-free survival time. In addition, we found that metformin and the structurally related compound aminoguanidine reduced DNA damage and ameliorated spontaneous chromosome breakage and radials in human FA patient-derived cells. Our results also indicate that aldehyde detoxification might be one of the mechanisms by which metformin reduces DNA damage in FA cells.
Assuntos
Carcinogênese/patologia , Anemia de Fanconi/tratamento farmacológico , Anemia de Fanconi/patologia , Hematopoese/efeitos dos fármacos , Metformina/farmacologia , Aldeídos/metabolismo , Animais , Contagem de Células Sanguíneas , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/patologia , Carcinogênese/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Quebra Cromossômica , Dano ao DNA , Dieta , Anemia de Fanconi/sangue , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/deficiência , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Guanidinas/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Humanos , Inativação Metabólica/efeitos dos fármacos , Metformina/administração & dosagem , Camundongos , Poli I-C/farmacologiaAssuntos
Falência Hepática Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Criança , Humanos , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/genética , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMO
JAK2, MPL, and CALR mutations, which underlie essential thrombocythemia (ET) in most adults, are infrequent in children. Consequently, additional tests are needed to confirm pediatric ET diagnoses. We report a child with suspected ET and normal JAK2, MPL, and CALR analyses. Serum thrombopoietin (TPO) was markedly elevated, leading to analysis of the TPO gene, TPHO, which contains an upstream open reading frame (uORF) known to repress THPO translation. Sequencing revealed a de novo, germline stopgain mutation in the uORF, explaining the elevated TPO and thrombocytosis. This finding suggests that screening TPO levels and, if elevated, THPO 5' UTR sequencing could be diagnostic.
Assuntos
Calreticulina/genética , Janus Quinase 2/genética , Receptores de Trombopoetina/genética , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/genética , Trombopoetina/sangue , Humanos , Lactente , Masculino , Contagem de Plaquetas , Trombopoetina/genéticaRESUMO
Secondary bone marrow fibrosis (BMF) is associated with many disease conditions in children, but its prevalence and characteristics have not been well elucidated. We present our experience with pediatric secondary BMF, in an attempt to characterize it in terms of underlying diagnoses, severity, and outcome. A retrospective chart review of patients diagnosed with secondary BMF by bone marrow aspirate and biopsy between January 1984 and April 2011 showed a total of 214 patients, the majority (67.1%) of whom had an underlying oncologic disease. At diagnosis, 87 patients (39.7%) had mild, 51 (23.3%) had moderate, and 33 (15.1%) had marked BMF; it was not quantified in 48 (21.9%) patients. An underlying oncologic disease was more frequently associated with marked fibrosis compared with hematologic and miscellaneous diagnoses. Follow-up posttreatment bone marrow aspirate assessments were available for 117 patients. The outcome ranges from worsening of fibrosis to complete resolution. A majority of these children (N=70/117, 60%) showed complete resolution of fibrosis. Of note, 27 patients had marked fibrosis at initial diagnosis and 16 (60%) of them showed complete resolution. These findings underscore the importance of appropriate treatment of the underlying disorder in reversing secondary BMF. Ours is the largest series of pediatric secondary BMF reported.
Assuntos
Mielofibrose Primária/etiologia , Mielofibrose Primária/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Prevalência , Mielofibrose Primária/epidemiologia , Estudos Retrospectivos , Adulto JovemAssuntos
Mielofibrose Primária/genética , Proteínas de Transporte Vesicular/deficiência , Anormalidades Múltiplas/genética , Transplante de Medula Óssea , Criança , Consanguinidade , Evolução Fatal , Feminino , Disgenesia Gonadal 46 XY/genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Linhagem , Fenótipo , Mielofibrose Primária/congênito , Mielofibrose Primária/terapia , Síndrome , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/fisiologiaRESUMO
The survival rate of pediatric acute myeloid leukemia (pAML) is currently around 60%. While survival has slowly increased over the past few decades, the development of novel agents likely to further improve survival for this heterogeneous patient population has been limited by gaps in the pAML pre-clinical pipeline. One of the major hurdles in evaluating new agents for pAML is the lack of pAML patient-derived xenograft (PDX) models. Unlike solid tumors and other types of leukemias, AML is notoriously hard to establish in mouse models, likely due in part to the need for specific human microenvironment elements. Our laboratory at TCH/BCM addressed this gap by establishing a systematic PDX workflow, leveraging advanced immunodeficient hosts and capitalizing on our high volume of pAML patients and close coordination between labs and clinical sections. Patients treated at TCH are offered the chance to participate in specimen banking protocols that allow blood and bone marrow collection as well as the collection of relevant clinical data. All patients who consent and have samples available are trialed for PDX development. In addition, samples from the Children's Oncology Group (COG) are also trialed for PDX generation. Serially transplanting PDX models are validated using short tandem repeat (STR) and characterized using both targeted DNA/RNA next generation sequencing and RNAseq. As of March 2023, this systematic approach has resulted in 26 serially transplanting models. Models have been shared with requesting labs to facilitate external pAML pre-clinical studies. Available PDX models can be located through the BCM PDX Portal. We expect our growing PDX resource to make a significant contribution to expediting the testing of promising novel therapeutics for pAML.