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1.
Haematologica ; 98(3): 424-7, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23144197

RESUMO

Acute promyelocytic leukemia is characterized by a chromosomal translocation involving the retinoic acid receptor alpha gene. To identify co-operating pathways to leukemogenesis, we crossed MRP8-PML/RARA transgenic mice with BXH-2 mice which harbor an endogenous murine leukemia virus that causes acute myeloid leukemia. Approximately half of the leukemias that arose in this cross showed features of acute promyelocytic leukemia. We identified 22 proviral insertion sites in acute promyelocytic-like leukemias and focused our analysis on insertion at Sox4, a HMG box transcription factor. Using a transplant model, co-operation between PML-RARα and Sox4 was confirmed with increased penetrance and reduced latency of disease. Interestingly, karyotypic analysis revealed cytogenetic changes suggesting that the factors combined to initiate but not complete leukemic transformation. The cooperation between these transcription factors is consistent with the paradigm of multiple routes to the disease and reinforces the concept that transcription factor networks are important therapeutic targets in myeloid leukemias.


Assuntos
Transformação Celular Neoplásica/genética , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição SOXC/genética , Animais , Medula Óssea/patologia , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Fígado/patologia , Linfonodos/patologia , Camundongos , Camundongos Transgênicos , Proteínas de Fusão Oncogênica/metabolismo , Ligação Proteica , Fatores de Transcrição SOXC/metabolismo , Baço/patologia
2.
J Exp Med ; 207(12): 2581-94, 2010 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-21059853

RESUMO

Gain of chromosome 8 is the most common chromosomal gain in human acute myeloid leukemia (AML). It has been hypothesized that gain of the MYC protooncogene is of central importance in trisomy 8, but the experimental data to support this are limited and controversial. In a mouse model of promyelocytic leukemia in which the MRP8 promoter drives expression of the PML-RARA fusion gene in myeloid cells, a Myc allele is gained in approximately two-thirds of cases as a result of trisomy for mouse chromosome 15. We used this model to test the idea that MYC underlies acquisition of trisomy in AML. We used a retroviral vector to drive expression of wild-type, hypermorphic, or hypomorphic MYC in bone marrow that expressed the PML-RARA transgene. MYC retroviruses cooperated in myeloid leukemogenesis and suppressed gain of chromosome 15. When the PML-RARA transgene was expressed in a Myc haploinsufficient background, we observed selection for increased copies of the wild-type Myc allele concomitant with leukemic transformation. In addition, we found that human myeloid leukemias with trisomy 8 have increased MYC. These data show that gain of MYC can contribute to the pathogenic effect of the most common trisomy of human AML.


Assuntos
Cromossomos Humanos Par 8 , Genes myc , Leucemia Promielocítica Aguda/genética , Trissomia , Animais , Células Cultivadas , Modelos Animais de Doenças , Humanos , Leucemia Promielocítica Aguda/etiologia , Camundongos , Proteínas de Fusão Oncogênica/genética , Recidiva
3.
Cancer Cell ; 9(2): 81-94, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16473276

RESUMO

RARA becomes an acute promyelocytic leukemia (APL) oncogene by fusion with any of five translocation partners. Unlike RARalpha, the fusion proteins homodimerize, which may be central to oncogenic activation. This model was tested by replacing PML with dimerization domains from p50NFkappaB (p50-RARalpha) or the rapamycin-sensitive dimerizing peptide of FKBP12 (F3-RARalpha). The X-RARalpha fusions recapitulated in vitro activities of PML-RARalpha. For F3-RARalpha, these properties were rapamycin sensitive. Although in vivo the artificial fusions alone are poor initiators of leukemia, p50-RARalpha readily cooperates with an activated mutant CDw131 to induce APL-like disease. These results demonstrate that the dimerization interface of RARalpha fusion partners is a critical element in APL pathogenesis while pointing to other features of PML for enhancing penetrance and progression.


Assuntos
Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Receptores do Ácido Retinoico/química , Receptores do Ácido Retinoico/metabolismo , Animais , Medula Óssea/patologia , Carcinógenos/metabolismo , Linhagem Celular , DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Dimerização , Regulação para Baixo/genética , Camundongos , Camundongos Transgênicos , Mutação/genética , Células Mieloides/metabolismo , Células Mieloides/patologia , Proteínas de Neoplasias/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Ligação Proteica , Estrutura Quaternária de Proteína , Receptores de Citocinas/metabolismo , Receptores do Ácido Retinoico/genética , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Repressoras/química , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Receptor alfa de Ácido Retinoico , Receptores X de Retinoides/metabolismo , Transcrição Gênica/genética
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