8p12 stem cell myeloproliferative disorder: the FOP-fibroblast growth factor receptor 1 fusion protein of the t(6;8) translocation induces cell survival mediated by mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt/mTOR pathways.

The FOP-fibroblast growth factor receptor 1 (FGFR1) fusion protein is expressed as a consequence of a t(6;8) (q27;p12) translocation associated with a stem cell myeloproliferative disorder with lymphoma, myeloid hyperplasia and eosinophilia. In the present report, we show that the fusion of the leucine-rich N-terminal region of FOP to the catalytic domain of FGFR1 results in conversion of murine hematopoietic cell line Ba/F3 to factor-independent cell survival via an antiapoptotic effect. This survival effect is dependent upon the constitutive tyrosine phosphorylation of FOP-FGFR1. Phosphorylation of STAT1 and of STAT3, but not STAT5, is observed in cells expressing FOP-FGFR1. The survival function of FOP-FGFR1 is abrogated by mutation of the phospholipase C gamma binding site. Mitogen-activated protein kinase (MAPK) is also activated in FOP-FGFR1-expressing cells and confers cytokine-independent survival to hematopoietic cells. These results demonstrate that FOP-FGFR1 is capable of protecting cells from apoptosis by using the same effectors as the wild-type FGFR1. Furthermore, we show that FOP-FGFR1 phosphorylates phosphatidylinositol 3 (PI3)-kinase and AKT and that specific inhibitors of PI3-kinase impair its ability to promote cell survival. In addition, FOP-FGFR1-expressing cells show constitutive phosphorylation of the positive regulator of translation p70S6 kinase; this phosphorylation is inhibited by PI3-kinase and mTOR (mammalian target of rapamycin) inhibitors. These results indicate that translation control is important to mediate the cell survival effect induced by FOP-FGFR1. Finally, FOP-FGFR1 protects cells from apoptosis by survival signals including BCL2 overexpression and inactivation of caspase-9 activity. Elucidation of signaling events downstream of FOP-FGFR1 constitutive activation provides insight into the mechanism of leukemogenesis mediated by this oncogenic fusion protein.

[Diagnostic validity of Zung's self-rating depression scale on primary care patients]. / Validez diagnóstica de la Self-Rating Depression Scale de Zung en pacientes de atención primaria.

INTRODUCTION: Although the Spanish version of the Zung's Self-Rating Depression Scale (SDS) is widely used, there are no studies about its validity as a diagnostic test in primary health care patients. METHODS: In a first phase, a sample of 350 consecutive primary care patients was assessed with the SDS. In a second phase, a subsample composed by all the positive test results and 1/3 of the negatives selected at random, was assessed with the modules of current Major Depressive Episode and Dysthymia of the Structured Clinical Interview for DSM-IV. Specific methods to avoid verification bias were used. Prevalence, sensitivity and specificity, predictive values, Receiver Operating Characteristic (ROC) curve, and Stratum Specific Likelihood Ratios (SSLR) were calculated. RESULTS: Prevalence estimations of major depression and dysthymia were 14,7% (IC95%: 10,7-18,7%) and 4,6% (IC95%: 2,4%-6,8%) respectively. Sensitivity and specificity to detect both diagnoses were 0,95 (IC95%: 0.87-1) and 0,74 (IC95%: 0,68-0,79). Area under ROC curve was 0,93. SSLR for scoring < 50 led to a post-test probability of 0.01. In the stratum with scoring > 69 the SSLR generated a post-test probability of 0.96. Less conclusive results were obtained by intermediate strata. CONCLUSIONS: The SDS is effective in primary care patients and shows operating characteristics comparable to other depression assessment scales. SSLR provides practical information to estimate the probability of suffer a depressive disorder in individual patients.

Validez diagnóstica de la Self-Rating Depression Scale de Zung en pacientes de atención primaria / Diagnostic validity of Zung's Self-Rating Depression Scale on primary care patients

Introducción: Aunque la versión española del cuestionario Self-Rating Depression Scale de Zung (SDS) goza de gran difusión, no existen estudios sobre su validez como prueba diagnóstica en pacientes de atención primaria. Metodología: En una primera fase evaluamos una muestra de 350 pacientes consecutivos de atención primaria con el SDS y, en una segunda fase, aplicamos la Structured Clinical Inteview for DSM-IV, en sus apartados de Episodio Depresivo Mayor y Distimia actuales, a una submuestra compuesta por todos los pacientes con resultado positivo en el test y 1/3 aleatorio de los negativos.Utilizamos metodología específica para evitar el sesgo de verificación y calculamos prevalencia, sensibilidad y especificidad, valores predictivos, curva Receiver Operating Characteristic (ROC) y Razones de Verosimilitud Específicas por Estratos (RVEE).Resultados: La prevalencia de depresión mayor fue de 14,7 por ciento (IC95 por ciento: 10,7 por ciento-18,7 por ciento) y la de distimia 4,6 por ciento (IC95 por ciento: 2,4 por ciento-6,8 por ciento). Los resultados de sensibilidad y especificidad para detectar ambos diagnósticos fueron 0,95 (IC95 por ciento: 0,87-1) y 0,74 (IC95 por ciento: 0,68-0,79). El área bajo la curva ROC fue de 0,93. La RVEE para las puntuaciones 69 la RVEE lleva a una probabilidad posttest de 0,96. Los estratos intermedios ofrecieron resultados menos concluyentes. Conclusiones: El SDS es eficaz en pacientes de atención primaria y muestra un comportamiento equiparable a otros cuestionarios de detección de la depresión. La aplicación de las RVEE puede ser muy práctica e informativa para estimar la probabilidad de padecer un trastorno depresivo en los pacientes individuales (AU)

The 8p12 myeloproliferative disorder. t(8;19)(p12;q13.3): a novel translocation involving the FGFR1 gene.

Translocations affecting the chromosomal locus 8p12 are hallmarks of an atypical stem cell myeloproliferative disorder. These events disrupt the fibroblast growth factor receptor 1 (FGFR1) gene and fuse the FGFR1 C-terminus catalytic domain with unrelated proteins. Here, we report on the characterization of the 19q13.3 locus as the fifth FGFR1 chromosomal partner.

FGFR1 is fused to the centrosome-associated protein CEP110 in the 8p12 stem cell myeloproliferative disorder with t(8;9)(p12;q33).

The hallmark of the 8p12 stem cell myeloproliferative disorder (MPD) is the disruption of the FGFR1 gene, which encodes a tyrosine kinase receptor for members of the fibroblast growth factor family. FGFR1 can be fused to at least 3 partner genes at chromosomal regions 6q27, 9q33, or 13q12. We report here the cloning of the t(8;9)(p12;q33) and the detection of a novel fusion betweenFGFR1 and the CEP110 gene, which codes for a novel centrosome-associated protein with a unique cell-cycle distribution. CEP110 is widely expressed at various levels in different tissues and is predicted to encode a 994-amino acid coiled-coil protein with 4 consensus leucine zippers [L-X(6)-L-X(6)-L-X(6)-L]. Both reciprocal fusion transcripts are expressed in the patient's cells. The CEP110-FGFR1 fusion protein encodes an aberrant tyrosine kinase of circa 150-kd, which retains most of CEP110 with the leucine zipper motifs and the catalytic domain of FGFR1. Transient expression studies show that the CEP110-FGFR1 protein has a constitutive kinase activity and is located within the cell cytoplasm. (Blood. 2000;95:1788-1796)

Characterization of FIM-FGFR1, the fusion product of the myeloproliferative disorder-associated t(8;13) translocation.

The t(8;13) translocation found in a rare type of stem cell myeloproliferative disorder generates a constitutively activated tyrosine kinase containing N-terminal sequence encoded by the FIM gene linked to the FGFR1 kinase domain. Here we have further characterized FIM and FIM-FGFR1 proteins. Firstly, we have studied their respective subcellular localization. We show that FIM has nuclear and nucleolar localization, whereas FIM-FGFR1 is mainly cytoplasmic. Within the nucleolus, FIM colocalizes with the upstream binding factor in interphasic cells, indicating that FIM may be involved in the regulation of rRNA transcription. We demonstrate that the targetting of FIM to the nucleus depends upon its C-terminal region, which is absent in the cytoplasmic FIM-FGFR1 protein. Secondly, we demonstrate that FIM-FGFR1 has constitutive dimerization capability mediated by the FIM N-terminal sequences. Finally, we show that FIM-FGFR1 promotes survival of pro-B Ba/F3 cells after interleukin-3 withdrawal, whereas ligand-activated FGFR1 induced not only cell survival but also interleukin-3 independence. Taken together, these results indicate that FIM-FGFR1 is activated by dimerization as a cytoplasmic kinase and suggest that FIM-FGFR1 partially signals through the FGFR1 pathways.

Fibroblast growth factor receptor 1 is fused to FIM in stem-cell myeloproliferative disorder with t(8;13).

Chromosome 8p11-12 is the site of a recurrent breakpoint in a myeloproliferative disorder that involves lymphoid (T- or B-cell), myeloid hyperplasia and eosinophilia, and evolves toward acute leukemia. This multilineage involvement suggests the malignant transformation of a primitive hematopoietic stem cell. In this disorder, the 8p11-12 region is associated with three different partners 6q27, 9q33, and 13q12. We describe here the molecular characterization of the t(8;13) translocation that involves the FGFR1 gene from 8p12, encoding a tyrosine kinase receptor for members of the fibroblast growth factor family, and a gene from 13q12, tentatively named FIM (Fused In Myeloproliferative disorders). FIM is related to DXS6673E, a candidate gene for X-linked mental retardation in Xq13.1; this defines a gene family involved in different human pathologies. The two reciprocal fusion transcripts, FIM/FGFR1 and FGFR1/FIM are expressed in the malignant cells. The FIM/FGFR1 fusion protein contains the FIM putative zinc finger motifs and the catalytic domain of FGFR1. We show that it has a constitutive tyrosine kinase activity.