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1.
Haematologica ; 108(5): 1222-1231, 2023 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-36384250

RESUMEN

Diamond-Blackfan anemia (DBA) is a ribosomopathy that is characterized by macrocytic anemia, congenital malformations, and early onset during childhood. Genetic studies have demonstrated that most patients carry mutations in one of the 20 related genes, most of which encode ribosomal proteins (RP). Treatment of DBA includes corticosteroid therapy, chronic red blood cell transfusion, and other forms of immunosuppression. Currently, hematopoietic stem cell transplantation is the only cure for DBA. Interestingly, spontaneous remissions occur in 10-20% of transfusion-dependent DBA patients. However, there is no consistent association between specific mutations and clinical manifestations. In the past decades, researchers have made significant progress in understanding the pathogenesis of DBA, but it remains unclear how the ubiquitous RP haploinsufficiency causes the erythroid-specific defect in hematopoiesis in DBA patients, and why there is a difference in penetrance and spontaneous remission among individuals who carry identical mutations. In this paper, we provide a comprehensive review of the development of DBA animal models and discuss the future research directions for these important experimental systems.


Asunto(s)
Anemia de Diamond-Blackfan , Animales , Anemia de Diamond-Blackfan/genética , Proteínas Ribosómicas/genética , Mutación , Modelos Animales , Hematopoyesis
2.
Blood ; 127(15): 1912-22, 2016 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-26764354

RESUMEN

Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric mixed myelodysplastic/myeloproliferative neoplasm (MDS/MPN). JMML leukemogenesis is linked to a hyperactivated RAS pathway, with driver mutations in the KRAS, NRAS, NF1, PTPN11, or CBL genes. Previous murine models demonstrated how those genes contributed to the selective hypersensitivity of JMML cells to granulocyte macrophage-colony-stimulating factor (GM-CSF), a unifying characteristic in the disease. However, it is unclear what causes the early death in children with JMML, because transformation to acute leukemia is rare. Here, we demonstrate that loss of Pten (phosphatase and tensin homolog) protein at postnatal day 8 in mice harboring Nf1 haploinsufficiency results in an aggressive MPN with death at a murine prepubertal age of 20 to 35 days (equivalent to an early juvenile age in JMML patients). The death in the mice was due to organ infiltration with monocytes/macrophages. There were elevated activities of protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) in cells at physiological concentrations of GM-CSF. These were more pronounced in mice with Nf1 haploinsufficiency than in littermates with wild-type Nf1,but this model is insufficient to cause cells to be GM-CSF hypersensitive. This new model represents a murine MPN model with features of a pediatric unclassifiable mixed MDS/MPN and mimics many clinical manifestations of JMML in terms of age of onset, aggressiveness, and organ infiltration with monocytes/macrophages. Our data suggest that the timing of the loss of PTEN protein plays a critical role in determining the disease severity in myeloid malignancies. This model may be useful for studying the pathogenesis of pediatric diseases with alterations in the Ras pathway.


Asunto(s)
Trastornos Mieloproliferativos/genética , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Animales , Trasplante de Médula Ósea , Movimiento Celular , Separación Celular , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Sistema de Señalización de MAP Quinasas , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Monocitos/metabolismo , Trastornos Mieloproliferativos/metabolismo , Neurofibromina 1/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células Madre/citología , Factores de Tiempo , Proteínas ras/metabolismo
3.
Blood ; 125(3): 516-24, 2015 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-25395418

RESUMEN

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of childhood associated with a poor prognosis. Recently, massively parallel sequencing has identified recurrent mutations in the SKI domain of SETBP1 in a variety of myeloid disorders. These lesions were detected in nearly 10% of patients with JMML and have been characterized as secondary events. We hypothesized that rare subclones with SETBP1 mutations are present at diagnosis in a large portion of patients who relapse, but are below the limits of detection for conventional deep sequencing platforms. Using droplet digital polymerase chain reaction, we identified SETBP1 mutations in 17/56 (30%) of patients who were treated in the Children's Oncology Group sponsored clinical trial, AAML0122. Five-year event-free survival in patients with SETBP1 mutations was 18% ± 9% compared with 51% ± 8% for those without mutations (P = .006).


Asunto(s)
Proteínas Portadoras/genética , Leucemia Mielomonocítica Juvenil/genética , Mutación/genética , Proteínas Nucleares/genética , Preescolar , Femenino , Estudios de Seguimiento , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Recién Nacido , Leucemia Mielomonocítica Juvenil/patología , Masculino , Estadificación de Neoplasias , Pronóstico , Tasa de Supervivencia
4.
Pediatr Blood Cancer ; 62(4): 629-36, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25704135

RESUMEN

BACKGROUND: Juvenile myelomonocytic leukemia (JMML) is not durably responsive to chemotherapy, and approximately 50% of patients relapse after hematopoietic stem cell transplant (HSCT). Here we report the activity and acute toxicity of the farnesyl transferase inhibitor tipifarnib, the response rate to 13-cis retinoic acid (CRA) in combination with cytoreductive chemotherapy, and survival following HSCT in children with JMML. PROCEDURE: Eighty-five patients with newly diagnosed JMML were enrolled on AAML0122 between 2001 and 2006. Forty-seven consented to receive tipifarnib in a phase II window before proceeding to a phase III trial of CRA in combination with fludarabine and cytarabine followed by HSCT and maintenance CRA. Thirty-eight patients enrolled only in the phase III trial. RESULTS: Overall response rate was 51% after tipifarnib and 68% after fludarabine/cytarabine/CRA. Tipifarnib did not increase pre-transplant toxicities. Forty-six percent of the 44 patients who received protocol compliant HSCT relapsed. Five-year overall survival was 55 ± 11% and event-free survival was 41 ± 11%, with no significant difference between patients who did or did not receive tipifarnib. CONCLUSIONS: Administration of tipifarnib in the window setting followed by HSCT in patients with newly diagnosed JMML was safe and yielded a 51% initial response rate as a single agent, but failed to reduce relapse rates or improve long-term overall survival.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Farnesil Difosfato Farnesil Transferasa/antagonistas & inhibidores , Leucemia Mielomonocítica Juvenil/tratamiento farmacológico , Quinolonas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Inhibidores Enzimáticos/administración & dosificación , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Isotretinoína/administración & dosificación , Leucemia Mielomonocítica Juvenil/enzimología , Leucemia Mielomonocítica Juvenil/mortalidad , Leucemia Mielomonocítica Juvenil/patología , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados
6.
Blood Adv ; 4(15): 3728-3740, 2020 08 11.
Artículo en Inglés | MEDLINE | ID: mdl-32777070

RESUMEN

It is not clear whether disrupted age-specific hematopoiesis contributes to the complex manifestations in leukemia patients who carry identical mutations, particularly in pediatric and adult patients with similar clinical characteristics. By studying a dual-age-specific mouse model, we demonstrate that (1) loss of Pten during the fetal-to-adult hematopoiesis switch (hematopoiesis switch) causes sustained fetal hematopoiesis, resulting in death in juvenile leukemia; (2) myeloid-biased hematopoiesis in juvenile mice is associated with the sustained fetal properties of hematopoietic stem cells (HSCs); (3) the age specificity of juvenile myelomonocytic leukemia depends on the copy number of Pten and Nf1; (4) single-allelic Pten deletion during the hematopoiesis switch causes constitutive activation of MAPK in juvenile mice with Nf1 loss of heterozygosity (LOH); and (5) Nf1 LOH causes monocytosis in juvenile mice with Pten haploinsufficiency but does not cause lethality until adulthood. Our data suggest that 1 copy of Pten is sufficient to maintain an intact negative-feedback loop of the Akt pathway and HSC function in reconstitution, despite MAPK being constitutively activated in juvenile Pten+/ΔNf1LOH mice. However, 2 copies of Pten are required to maintain the integrity of the MAPK pathway in juvenile mice with Nf1 haploinsufficiency. Our data indicate that previous investigations of Pten function in wild-type mice may not reflect the impact of Pten loss in mice with Nf1 mutations or other genetic defects. We provide a proof of concept that disassociated age-specific hematopoiesis contributes to leukemogenesis and pediatric demise.


Asunto(s)
Hematopoyesis , Leucemia , Adulto , Factores de Edad , Animales , Niño , Modelos Animales de Enfermedad , Células Madre Hematopoyéticas , Humanos , Leucemia/genética , Ratones
7.
J Cell Biochem ; 105(4): 1092-108, 2008 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-18816594

RESUMEN

mrtl (myc-related translation/localization regulatory factor) is a previously uncharacterized protein synthesized from the first open reading frame contained within the human c-myc P0 transcript, approximately 800 nucleotides upstream of the Myc coding sequence. The mrtl protein, 114 amino acids in length, is projected to contain an N-terminal transmembrane domain and a highly charged C-terminal interaction domain with homology to numerous RNA-binding proteins. Using monoclonal antibodies raised against the hydrophilic C-terminal domain, endogenous mrtl was visualized in human breast tumor cell lines and primary mammary epithelial cells at the nuclear envelope and contiguous endoplasmic/nucleoplasmic reticulum. mrtl colocalizes and coimmunoprecipitates with translation initiation factor eIF2alpha and the 40S ribosomal protein RACK1, and appears capable of binding specifically to the c-myc RNA. Inducible ectopic overexpression of wild-type mrtl interferes with the function of endogenous mrtl, which results in loss of Myc from the nucleus. Furthermore, treatment of cells with a peptide derived from the C-terminal domain displaces endogenous mrtl and causes a dramatic reduction in total cellular Myc protein levels. Together with our previous work demonstrating complete loss of tumorigenicity in association with ectopic expression of the c-myc P0 5'-UTR (containing the mrtl coding sequence), these results suggest that mrtl may serve an important function in regulating Myc translation and localization to the nucleus, perhaps ultimately contributing to the role of the c-myc locus in oncogenesis.


Asunto(s)
Proteínas Portadoras , Retículo Endoplásmico/química , Matriz Nuclear/química , Proteínas Proto-Oncogénicas c-myc/genética , Transporte Activo de Núcleo Celular , Neoplasias de la Mama/etiología , Neoplasias de la Mama/patología , Proteínas Portadoras/análisis , Proteínas Portadoras/genética , Proteínas Portadoras/fisiología , Línea Celular Tumoral , Femenino , Humanos , Glándulas Mamarias Humanas/citología , Sistemas de Lectura Abierta , Biosíntesis de Proteínas , Estructura Terciaria de Proteína , ARN Mensajero/metabolismo , Proteínas de Unión al ARN
8.
Cell Signal ; 50: 72-79, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-29964149

RESUMEN

Constitutively activated MAPK and AKT signaling pathways are often found in solid tumors and leukemias. PTEN is one of the tumor suppressors that are frequently found deficient in patients with late-stage cancers or leukemias. In this study we demonstrate that a MAPK inhibitor, PD98059, inhibits both AKT and ERK phosphorylation in a human myeloid leukemia cell line (TF-1), but not in PTEN-deficient leukemia cells (TF-1a). Ectopic expression of wild-type PTEN in myeloid leukemia cells restored cytokine responsiveness at physiological concentrations of GM-CSF (<0.02 ng/mL) and significantly improved cell sensitivity to MAPK inhibitor. We also found that Early Growth Response 1 (EGR1) was constitutively over-expressed in cytokine-independent TF-1a cells, and ectopic expression of PTEN down-regulated EGR1 expression and restored dynamics of EGR1 expression in response to GM-CSF stimulation. Data from primary bone marrow cells from mice with Pten deletion further supports that PTEN is indispensible for myeloid leukemia cells in response to MAPK inhibitors. Finally, We demonstrate that the absence of EGR1 expression dynamics in response to GM-CSF stimulation is one of the mechanisms underlying drug resistance to MAPK inhibitors in leukemia cells with PTEN deficiency. Our data suggest a novel mechanism of PTEN in regulating expression of EGR1 in hematopoietic cells in response to cytokine stimulation. In conclusion, this study demonstrates that PTEN is dispensable for myeloid leukemia cells in response to MAPK inhibitors, and PTEN regulates EGR1 expression and contributes to the cytokine sensitivity in leukemia cells.


Asunto(s)
Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/metabolismo , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Fosfohidrolasa PTEN/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Animales , Línea Celular , Regulación hacia Abajo/efectos de los fármacos , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Células HEK293 , Humanos , Ratones , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos
9.
Blood Adv ; 2(8): 859-870, 2018 04 24.
Artículo en Inglés | MEDLINE | ID: mdl-29666049

RESUMEN

Uncovering the cellular and molecular mechanisms by which hematopoietic stem cell (HSC) self-renewal is regulated can lead to the development of new strategies for promoting ex vivo HSC expansion. Here, we report the discovery that alternative (M2)-polarized macrophages (M2-MΦs) promote, but classical (M1)-polarized macrophages (M1-MΦs) inhibit, the self-renewal and expansion of HSCs from mouse bone marrow (BM) in vitro. The opposite effects of M1-MΦs and M2-MΦs on mouse BM HSCs were attributed to their differential expression of nitric oxide synthase 2 (NOS2) and arginase 1 (Arg1), because genetic knockout of Nos2 and Arg1 or inhibition of these enzymes with a specific inhibitor abrogated the differential effects of M1-MΦs and M2-MΦs. The opposite effects of M1-MΦs and M2-MΦs on HSCs from human umbilical cord blood (hUCB) were also observed when hUCB CD34+ cells were cocultured with M1-MΦs and M2-MΦs generated from hUCB CD34- cells. Importantly, coculture of hUCB CD34+ cells with human M2-MΦs for 8 days resulted in 28.7- and 6.6-fold increases in the number of CD34+ cells and long-term SCID mice-repopulating cells, respectively, compared with uncultured hUCB CD34+ cells. Our findings could lead to the development of new strategies to promote ex vivo hUCB HSC expansion to improve the clinical utility and outcome of hUCB HSC transplantation and may provide new insights into the pathogenesis of hematological dysfunctions associated with infection and inflammation that can lead to differential macrophage polarization.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Autorrenovación de las Células/efectos de los fármacos , Células Madre Hematopoyéticas/citología , Macrófagos/fisiología , Animales , Arginasa/metabolismo , Técnicas de Cocultivo , Sangre Fetal/citología , Humanos , Masculino , Ratones , Óxido Nítrico Sintasa de Tipo II/metabolismo
10.
Endocr Relat Cancer ; 23(9): 677-90, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27402613

RESUMEN

The emerging links between breast cancer and metabolic dysfunctions brought forth by the obesity pandemic predict a disproportionate early disease onset in successive generations. Moreover, sensitivity to chemotherapeutic agents may be influenced by the patient's metabolic status that affects the disease outcome. Maternal metabolic stress as a determinant of drug response in progeny is not well defined. Here, we evaluated mammary tumor response to doxorubicin in female mouse mammary tumor virus-Wnt1 transgenic offspring exposed to a metabolically compromised environment imposed by maternal high-fat diet. Control progeny were from dams consuming diets with regular fat content. Maternal high-fat diet exposure increased tumor incidence and reduced tumor latency but did not affect tumor volume response to doxorubicin, compared with control diet exposure. However, doxorubicin-treated tumors from high-fat-diet-exposed offspring demonstrated higher proliferation status (Ki-67), mammary stem cell-associated gene expression (Notch1, Aldh1) and basal stem cell-like (CD29(hi)CD24(+)) epithelial subpopulation frequencies, than tumors from control diet progeny. Notably, all epithelial subpopulations (CD29(hi)CD24(+), CD29(lo)CD24(+), CD29(hi)CD24(+)Thy1(+)) in tumors from high-fat-diet-exposed offspring were refractory to doxorubicin. Further, sera from high-fat-diet-exposed offspring promoted sphere formation of mouse mammary tumor epithelial cells and of human MCF7 cells. Untargeted metabolomics analyses identified higher levels of kynurenine and 2-hydroxyglutarate in plasma of high-fat diet than control diet offspring. Kynurenine/doxorubicin co-treatment of MCF7 cells enhanced the ability to form mammosphere and decreased apoptosis, relative to doxorubicin-only-treated cells. Maternal metabolic dysfunctions during pregnancy and lactation may be targeted to reduce breast cancer risk and improve early drug response in progeny, and may inform clinical management of disease.


Asunto(s)
Antineoplásicos/uso terapéutico , Dieta Alta en Grasa , Doxorrubicina/uso terapéutico , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Animales , Resistencia a Antineoplásicos , Células Epiteliales/patología , Femenino , Humanos , Células MCF-7 , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Transgénicos , Estrés Oxidativo , Carga Tumoral/efectos de los fármacos , Proteína Wnt1/genética
11.
Nat Genet ; 47(11): 1326-1333, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26457647

RESUMEN

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 or CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and could therefore be candidates for experimental therapies. In addition, few molecular pathways aside from the RAS-MAPK pathway have been identified that could serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia to expand knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, splicing, Polycomb repressive complex 2 (PRC2) and transcription. Notably, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Leucemia Mielomonocítica Juvenil/genética , Mutación , Transducción de Señal/genética , Enfermedad Aguda , Niño , Preescolar , Variaciones en el Número de Copia de ADN , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Lactante , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/genética , Leucemia Mielomonocítica Juvenil/diagnóstico , Masculino , Pronóstico
13.
Pediatr Blood Cancer ; 44(2): 142-6, 2005 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-15390271

RESUMEN

BACKGROUND: Activating mutations of FLT3 have been identified in multiple myeloid malignancies. Two types of activating mutations have been described: (1) the internal tandem duplication (FLT3-ITD) and (2) point mutations within the activating loop (FLT3-ALM). Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative disorder of early childhood. Mutations and other genetic abnormalities of RAS, NF1, and PTPN11 have been implicated as causative events in JMML, but approximately 25% of JMML patients harbor none of these abnormalities. We investigated whether FLT3 mutations might also contribute to JMML pathogenesis, and if present, whether FLT3 status would correlate with disease natural history and prognosis. PROCEDURES: Genomic DNA was isolated from peripheral blood and bone marrow samples of 60 patients meeting international JMML diagnostic criteria. Samples were analyzed for FLT3-ITD and FLT3-ALM using polymerase chain reaction and restriction endonuclease digestion. RESULTS: FLT3-ALM was found in 1/60 (1.7%) patients analyzed. Direct sequencing confirmed a C836G mutation. Clinical and laboratory characteristics of the JMML patient with the FLT3-ALM did not differ from the remainder of the cohort. No FLT3-ITD mutations were detected. CONCLUSIONS: This first reported mutational analysis for both FLT3-ITD and FLT3-ALM performed in JMML documents the presence of FLT3 mutations within JMML, but at a sufficiently low prevalence as to be clinically insignificant for most patients. Despite the poor prognosis and limited therapeutic options for JMML patients with refractory disease, compassionate therapy with targeted FLT3 inhibitors should not be considered in this patient population until adequate safety and efficacy data become available.


Asunto(s)
Leucemia Mielomonocítica Crónica/genética , Mutación Puntual , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Niño , Preescolar , Humanos , Lactante , Pérdida de Heterocigocidad , Secuencias Repetidas en Tándem , Tirosina Quinasa 3 Similar a fms
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