RESUMEN
The blood system serves as a key model for cell differentiation and cancer. It is orchestrated by precise spatiotemporal expression of crucial transcription factors. One of the key master regulators in the hematopoietic systems is PU.1. Reduced levels of PU.1 are characteristic for human acute myeloid leukemia (AML) and are known to induce AML in mouse models. Here, we show that transcriptional downregulation of PU.1 is an active process involving an alternative promoter in intron 3 that is induced by RUNX transcription factors driving noncoding antisense transcription. Core-binding factor (CBF) fusions RUNX1-ETO and CBFß-MYH11 in t(8;21) and inv(16) AML, respectively, activate the PU.1 antisense promoter that results in a shift from sense toward antisense transcription and myeloid differentiation blockade. In patients with CBF-AML, we found that an elevated antisense/sense transcript and promoter accessibility ratio represents a hallmark compared with normal karyotype AML or healthy CD34+ cells. Competitive interaction of an enhancer with the proximal or the antisense promoter forms a binary on/off switch for either myeloid or T-cell development. Leukemic CBF fusions thus use a physiological mechanism used by T cells to decrease sense transcription. Our study is the first example of a sense/antisense promoter competition as a crucial functional switch for gene expression perturbation by oncogenes. Hence, this disease mechanism reveals a previously unknown Achilles heel for future precise therapeutic targeting of oncogene-induced chromatin remodeling.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad beta del Factor de Unión al Sitio Principal/genética , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogénicas/genética , Transactivadores/genética , Elementos sin Sentido (Genética)/genética , Línea Celular Tumoral , Fusión Génica , Humanos , Proteínas de Fusión Oncogénica/genética , Regiones Promotoras Genéticas , Proteína 1 Compañera de Translocación de RUNX1/genética , Células Tumorales CultivadasRESUMEN
BACKGROUND: Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFRß. Blocking PDGFRß kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive. METHODS AND RESULTS: In a transgenic mouse model that mimics PDGFRß-driven human ALCL in vivo, we identify PDGFRß as a driver of aggressive tumor growth. Mechanistically, PDGFRß induces the pro-survival factor Bcl-xL and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo. CONCLUSIONS: We therefore propose PDGFRß as a novel biomarker and introduce PDGFRß-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFRß or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK+ ALCL patients.
Asunto(s)
Linfoma Anaplásico de Células Grandes , Receptor beta de Factor de Crecimiento Derivado de Plaquetas , Factor de Transcripción STAT3 , Factor de Transcripción STAT5 , Quinasa de Linfoma Anaplásico , Animales , Carcinogénesis/metabolismo , Línea Celular Tumoral , Humanos , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patología , Ratones , Fosforilación , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/farmacología , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT5/genética , Transducción de SeñalRESUMEN
AIMS: Cancer patients often present with psychological symptoms that affect their quality of life, physical health outcomes and survival. Two of the most frequent psychiatric comorbidities are anxiety and depression. However, the prevalence of these disorders among cancer patients remains unclear, as studies frequently report varying rates. In the present study, we aimed to provide robust point estimates for the prevalence of anxiety and depression for both a mixed cancer sample and for 13 cancer types separately, considering confounding variables. METHODS: In a sample of 7509 cancer outpatients (51.4% female), we used the Hospital Anxiety and Depression Scale to assess rates of anxiety and depression. Applying ordinal logistic regression models, we compared the prevalence of anxiety and depression between different cancer types, controlling for age and gender. RESULTS: About one third of our sample showed symptoms of anxiety (35.2%) or depression (27.9%), and every sixth patient had a very likely psychiatric condition, with women being more frequently affected. Elderly patients more often showed signs of depression. The prevalence of anxiety and depression was significantly higher in lung and brain cancer patients, than in other cancer patients. Lowest depression rates were found in breast cancer patients. CONCLUSIONS: The prevalence of anxiety and depression is high in cancer patients. Type of cancer is an important predictor for anxiety and depressive symptoms, with lung and brain cancer patients being highly burdened. Considering a personalised medicine approach, physicians should take into account the high prevalence of psychiatric comorbidities and include psychiatric consultations in the treatment plan.
Asunto(s)
Neoplasias Encefálicas , Neoplasias de la Mama , Neoplasias Hematológicas , Anciano , Ansiedad/epidemiología , Ansiedad/psicología , Neoplasias de la Mama/epidemiología , Estudios Transversales , Depresión/epidemiología , Depresión/psicología , Femenino , Neoplasias Hematológicas/epidemiología , Humanos , Masculino , Prevalencia , Calidad de VidaRESUMEN
Bleeding because of impaired platelet function is a major side effect of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. We quantitatively assessed ristocetin-induced platelet aggregation (RIPA) in 64 patients with chronic lymphocytic leukemia (CLL) under ibrutinib at 287 time points. Eighty-seven bleeding episodes in 39 patients were registered (85 Common Toxicity Criteria (CTC) grade 1 or 2, 2 CTC grade 3) during a median observation period of 10.9 months. At times of bleeding, RIPA values were significantly lower (14 vs 28 U; P<0.0001). RIPA was impaired in patients receiving concomitant antiplatelet therapy or anticoagulation (14 vs 25 U, P=0.005). A gradual decline of median RIPA values was observed with increasing bleeding severity. Importantly, no CTC grade 2 or 3 bleeding were observed with RIPA values of >36 U. Sequential monitoring indicated a decrease of RIPA values from a median of 17 to 9 U within 2 weeks after initiation of treatment as well as an increase above the critical threshold of 36 U within 7 days when ibrutinib was paused. Low RIPA values were similar during treatment with another BTK inhibitor, CC292. Quantitative assessment of platelet function is a practical tool to monitor bleeding tendency under BTK-inhibitor therapy.
Asunto(s)
Hemorragia/inducido químicamente , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Agregación Plaquetaria/efectos de los fármacos , Pirazoles/efectos adversos , Pirimidinas/efectos adversos , Ristocetina/farmacología , Adenina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Monitoreo de Drogas/métodos , Femenino , Hemorragia/tratamiento farmacológico , Humanos , Leucemia Linfocítica Crónica de Células B/complicaciones , Masculino , Persona de Mediana Edad , Piperidinas , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificaciónRESUMEN
One of the main functions of the tumor necrosis factor receptor (TNFR) family is induction of apoptosis. CD30, a member of the TNFR superfamily is overexpressed in highly proliferating tumors such as anaplastic large cell lymphoma (ALCL) and Hodgkin's lymphoma (HL). CD30 stimulation leads to apoptosis and growth arrest in cultured ALCL, but not in Hodgkin-Reed-Sternberg cells. To identify changes in the transcriptional program responsible for these opposing effects, we performed gene expression analysis in CD30-stimulated ALCL (Karpas 299) and HL (KM-H2) cell lines using cDNA microarrays. Selected genes were validated by real-time PCR. Hierarchical clustering was applied to the whole dataset and separated the cell lines clearly with respect to their origin. In HL, there were only minor CD30-specific alterations, whereas ALCL unequivocally showed a pronounced CD30-specific transcriptional response. Ninety-three genes (6.6% of total) were deregulated by more than a factor of two after CD30 stimulation in ALCL cells. The majority of genes identified are involved in cell cycle regulation and apoptosis. mRNA expression patterns further indicate that in contrast to HL, CD30 stimulation in ALCL induces cell death via the CD95-CD95 ligand (CD95L) pathway and the TNF-R1/TNF-R2 crosstalk. These data provide a detailed view on the transcriptional changes upon CD30 stimulation and may explain the observed functional differences of HL and ALCL.
Asunto(s)
Apoptosis/genética , Ciclo Celular/genética , Regulación Leucémica de la Expresión Génica , Antígeno Ki-1 , Linfoma de Células B Grandes Difuso/genética , Transducción de Señal , Línea Celular Tumoral , Perfilación de la Expresión Génica , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/metabolismo , Humanos , Antígeno Ki-1/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Infectious complications are frequent events in patients undergoing high-dose cytotoxic chemotherapy with subsequent autologous peripheral blood stem cell transplantation (PBSCT). To evaluate whether a single subcutaneous injection of pegfilgrastim (6 mg) is as safe and effective as daily filgrastim (5 mug/kg/day), 60 consecutive autologous stem cell transplantations performed for various haematological malignancies have been analysed. In total, 24 patients undergoing 30 consecutive PBSCT received a single subcutaneous injection of 6 mg pegfilgrastim on day 5 after transplantation and were compared retrospectively with 30 patients receiving 5 mug/kg/day of filgrastim starting from day 7 post transplantation. The mean duration of grade 4 neutropenia in the pegfilgrastim and filgrastim groups was 8.3 and 9.5 days, respectively (P=0.047). The results of the two groups were not significantly different for incidence of febrile neutropenia and toxicity profile. However, duration of febrile neutropenia (1.6 vs 3.0 days) and total days of fever (1.73 vs 4.1) were different (P=0.017 and 0.003, respectively), favouring the pegfilgrastim arm. Consequently, a higher incidence of transplants with documented infectious complications associated with the filgrastim group could be observed (56 vs 26%) (P=0.02). A single injection of pegfilgrastim administered at day 5 post transplant shows comparable safety and efficacy profiles to daily injections of filgrastim.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Neoplasias Hematológicas/terapia , Trastornos Linfoproliferativos/terapia , Neutropenia/tratamiento farmacológico , Trasplante de Células Madre de Sangre Periférica , Adulto , Anciano , Femenino , Filgrastim , Neoplasias Hematológicas/complicaciones , Humanos , Inyecciones Subcutáneas , Trastornos Linfoproliferativos/complicaciones , Masculino , Persona de Mediana Edad , Neutropenia/etiología , Polietilenglicoles , Proteínas Recombinantes , Trasplante AutólogoRESUMEN
BACKGROUND AND OBJECTIVES: Host- or donor-derived alloimmune thrombocytopenia can develop after non-myeloablative allogeneic haematopoietic stem cell transplantation (HSCT). We report the first case of host-derived HPA-1a antibodies. CASE REPORT: A 52-year-old male patient received HSCT from his human leucocyte antigen (HLA)-A, -B, -C, -DR identical brother after reduced intensity conditioning. Bilinear engraftment around day 12 was accompanied by a continuous decrease of platelet counts. We investigated for platelet antibodies because of a progressive decline of platelet counts and refractoriness to platelet transfusions. METHODS: The patient's serum was tested by enzyme-linked immunosorbent assay (ELISA), a solid phase assay and monoclonal antibody-specific immobilization of platelet antigens (MAIPA) assay. Recipient's DNA from the time before HSCT and donor's DNA were genotyped for human platelet antigens. RESULTS: Serum obtained on day 15 after HSCT reacted strongly with the donor's platelets due to host-derived anti-HPA-1a- and anti-HLA I antibodies. Serum samples from days 39, 45 and 65 after HSCT contained only anti-HLA I; no antibodies were detectable on day 149. Platelet counts increased on day 20 spontaneously. The decrease of the antibodies accompanied by the increase of the platelet counts suggests progressive elimination of residual host cells. CONCLUSIONS: The HPA-1a antibodies affected thrombopoietic engraftment and the success of platelet transfusions.