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1.
Nat Immunol ; 14(5): 437-45, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23563689

RESUMO

How hematopoietic stem cells (HSCs) coordinate the regulation of opposing cellular mechanisms such as self-renewal and differentiation commitment remains unclear. Here we identified the transcription factor and chromatin remodeler Satb1 as a critical regulator of HSC fate. HSCs lacking Satb1 had defective self-renewal, were less quiescent and showed accelerated lineage commitment, which resulted in progressive depletion of functional HSCs. The enhanced commitment was caused by less symmetric self-renewal and more symmetric differentiation divisions of Satb1-deficient HSCs. Satb1 simultaneously repressed sets of genes encoding molecules involved in HSC activation and cellular polarity, including Numb and Myc, which encode two key factors for the specification of stem-cell fate. Thus, Satb1 is a regulator that promotes HSC quiescence and represses lineage commitment.


Assuntos
Células-Tronco Hematopoéticas/fisiologia , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Animais , Diferenciação Celular/genética , Linhagem da Célula/genética , Polaridade Celular/genética , Sobrevivência Celular/genética , Células Cultivadas , Montagem e Desmontagem da Cromatina/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo
2.
Blood ; 126(9): 1118-27, 2015 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-26170031

RESUMO

Poor clinical outcome of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) has been attributed to failure of current chemotherapeutic regimens to target leukemic stem cells. We recently identified p21-activated kinase (PAK1) as a downstream effector molecule of H2.0-like homeobox (HLX), a gene functionally relevant for AML pathogenesis. In this study, we find that inhibition of PAK1 activity by small molecule inhibitors or by RNA interference leads to profound leukemia inhibitory effects both in vitro and in vivo. Inhibition of PAK1 induces differentiation and apoptosis of AML cells through downregulation of the MYC oncogene and a core network of MYC target genes. Importantly, we find that inhibition of PAK1 inhibits primary human leukemic cells including immature leukemic stem cell-enriched populations. Moreover, we find that PAK1 upregulation occurs during disease progression and is relevant for patient survival in MDS. Our studies highlight PAK1 as a novel target in AML and MDS and support the use of PAK1 inhibitors as a therapeutic strategy in these diseases.


Assuntos
Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Quinases Ativadas por p21/antagonistas & inibidores , Quinases Ativadas por p21/genética , Animais , Apoptose , Linhagem Celular Tumoral , Genes myc , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Terapia de Alvo Molecular , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Interferência de RNA , Terapêutica com RNAi , Quinases Ativadas por p21/metabolismo
3.
Stem Cells Transl Med ; 2(2): 143-50, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23349328

RESUMO

Recent experimental evidence has shown that acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) arise from transformed immature hematopoietic cells following the accumulation of multiple stepwise genetic and epigenetic changes in hematopoietic stem cells and committed progenitors. The series of transforming events initially gives rise to preleukemic stem cells (pre-LSC), preceding the formation of fully transformed leukemia stem cells (LSC). Despite the established use of poly-chemotherapy, relapse continues to be the most common cause of death in AML and MDS. The therapeutic elimination of all LSC, as well as pre-LSC, which provide a silent reservoir for the re-formation of LSC, will be essential for achieving lasting cures. Conventional sequencing and next-generation genome sequencing have allowed us to describe many of the recurrent mutations in the bulk cell populations in AML and MDS, and recent work has also focused on identifying the initial molecular changes contributing to leukemogenesis. Here we review recent and ongoing advances in understanding the roles of pre-LSC, and the aberrations that lead to pre-LSC formation and subsequent LSC transformation.


Assuntos
Transformação Celular Neoplásica/genética , Leucemia/patologia , Células-Tronco Neoplásicas/patologia , Pré-Leucemia/patologia , Regulação Leucêmica da Expressão Gênica/fisiologia , Humanos , Leucemia/genética , Biologia Molecular , Células-Tronco Neoplásicas/fisiologia , Pré-Leucemia/genética
4.
Cancer Cell ; 22(2): 194-208, 2012 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-22897850

RESUMO

Homeobox domain-containing transcription factors are important regulators of hematopoiesis. Here, we report that increased levels of nonclustered H2.0-like homeobox (HLX) lead to loss of functional hematopoietic stem cells and formation of aberrant progenitors with unlimited serial clonogenicity and blocked differentiation. Inhibition of HLX reduces proliferation and clonogenicity of leukemia cells, overcomes the differentiation block, and leads to prolonged survival. HLX regulates a transcriptional program, including PAK1 and BTG1, that controls cellular differentiation and proliferation. HLX is overexpressed in 87% of patients with acute myeloid leukemia (AML) and independently correlates with inferior overall survival (n = 601, p = 2.3 × 10(-6)). Our study identifies HLX as a key regulator in immature hematopoietic and leukemia cells and as a prognostic marker and therapeutic target in AML.


Assuntos
Hematopoese , Proteínas de Homeodomínio/metabolismo , Leucemia Mieloide Aguda/patologia , Fatores de Transcrição/metabolismo , Animais , Antígenos CD34/metabolismo , Ciclo Celular/genética , Morte Celular , Diferenciação Celular/genética , Células Clonais , Regulação para Baixo/genética , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Proteínas de Homeodomínio/antagonistas & inibidores , Proteínas de Homeodomínio/genética , Humanos , Lentivirus/genética , Leucemia Mieloide Aguda/genética , Camundongos , Monócitos/metabolismo , Monócitos/patologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Análise de Sobrevida , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Transcriptoma/genética
5.
J Exp Med ; 207(1): 223-35, 2010 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-20065066

RESUMO

We describe a quantitative model for assessing the cytolytic activity of antigen-specific CD8+ T cells in vitro and in vivo in which the concentration of antigen-specific CD8+ T cells determines the efficiency with which these cells kill cognate antigen-expressing melanoma cells in packed cell pellets, in three-dimensional collagen-fibrin gels in vitro, and in established melanomas in vivo. In combination with a clonogenic assay for melanoma cells, collagen-fibrin gels are 4,500-5,500-fold more sensitive than the packed cell pellet-type assays generally used to measure CD8+ T cell cytolytic activity. An equation previously used to describe neutrophil bactericidal activity in vitro and in vivo also describes antigen-specific CD8+ T cell-mediated cytolysis of cognate antigen-expressing melanoma cells in collagen-fibrin gels in vitro and in transplanted tumors in vivo. We have used this equation to calculate the critical concentration of antigen-specific CD8+ T cells, which is the concentration of these cells required to hold constant the concentration of a growing population of cognate antigen-expressing melanoma cells. It is approximately 3.5x10(5)/ml collagen-fibrin gel in vitro and approximately 3x10(6)/ml or /g melanoma for previously published studies of ex vivo-activated adoptively transferred tumor antigen-specific CD8+ T cell killing of cognate antigen-expressing melanoma cells in established tumors in vivo. The antigen-specific CD8+ T cell concentration required to kill 100% of 2x10(7)/ml cognate antigen-expressing melanoma cells in collagen fibrin gels is >or=10(7)/ml of gel.


Assuntos
Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Melanoma/imunologia , Animais , Antígenos de Neoplasias/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunidade Celular/genética , Imunidade Celular/imunologia , Melanoma/genética , Camundongos , Camundongos Transgênicos
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