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1.
J Pediatr Hematol Oncol ; 38(1): 49-52, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26599988

RESUMO

Allogeneic stem cell transplantation is a curative treatment for severe congenital neutropenia (SCN). However, a standard conditioning regimen and donor source have not been established. We report 3 consecutive cases of SCN who were successfully treated by cord blood transplantation (CBT) with reduced-intensity conditioning consisting of fludarabine, melphalan, and low-dose total body irradiation. All cases achieved complete donor chimerism without severe infectious complications and have maintained normal neutrophil counts for between 3 and 9 years after CBT. These results suggest that CBT with reduced-intensity conditioning can be an alternative therapy for SCN when human leukocyte antigen-matched bone marrow donor is unavailable.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Neutropenia/congênito , Condicionamento Pré-Transplante/métodos , Síndrome Congênita de Insuficiência da Medula Óssea , Feminino , Humanos , Masculino , Neutropenia/cirurgia
2.
Int J Hematol ; 81(4): 310-4, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15914361

RESUMO

A 26-year-old man with idiopathic hypereosinophilic syndrome (HES) was treated with imatinib mesylate following a 5-year history of prednisolone therapy. The patient had hypereosinophilia (absolute eosinophil counts >1500/microL) occurring in cyclic oscillations as well as histologically diagnosed eosinophilic vasculitis, bursitis, and periodic soft-tissue swellings. Laboratory data revealed high levels of serum tryptase and increased numbers of mast cells in the bone marrow, but serum interleukin 5 levels were within the normal range. The disease initially responded well to 100 mg/day of imatinib mesylate but recurred 8 weeks later. Thereafter, a daily 200-mg dose was temporarily effective. Despite the response to imatinib, the FIP1L1-PDGFRA fusion gene was not detected by fluorescence in situ hybridization analysis. Additional molecular and cytogenetic studies showed neither translocations of platelet-derived growth factor receptor (PDGFR) genes nor mutations in the c-KIT or the PDGFR genes. Although imatinib mesylate is a choice of treatment for patients with HES, its precise molecular mechanism in individual cases remains to be clarified.


Assuntos
Antineoplásicos/farmacologia , Síndrome Hipereosinofílica/tratamento farmacológico , Piperazinas/farmacologia , Pirimidinas/farmacologia , Adulto , Benzamidas , Análise Mutacional de DNA , Humanos , Mesilato de Imatinib , Masculino , Receptores do Fator de Crescimento Derivado de Plaquetas/genética , Recidiva , Resultado do Tratamento
3.
Blood ; 105(11): 4298-307, 2005 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-15713794

RESUMO

AML1/Runx1 is a frequent target of human leukemia-associated gene aberration and encodes a transcription factor with nonredundant biologic functions in initial development of definitive hematopoiesis, T-cell development, and steady-state platelet production. AML1/Runx1 and 2 closely related family genes, AML2/Runx3 and AML3/Runx2/Cbfa1, present in mammals, comprise the Runt-domain transcription factor family. Although they have similar structural and biochemical properties, gene-targeting experiments have identified distinct biologic roles. To directly determine the presence of functional overlap among runt-related transcription factor (Runx) family molecules, we replaced the C-terminal portion of acute myeloid leukemia 1 (AML1) with that derived from its family members, which are variable in contrast to conserved Runt domain, using the gene knock-in method. We found that C-terminal portions of either AML2 or AML3 could functionally replace that of AML1 for myeloid development in culture and within the entire mouse. However, while AML2 substituted for AML1 could effectively rescue lymphoid lineages, AML3 could not, resulting in a smaller thymus and lymphoid deficiency in peripheral blood. Substitution by the C-terminal portion of AML3 also led to high infantile mortality and growth retardation, suggesting that AML1 has as yet unidentified effects on these phenotypes. Thus, the C-terminal portions of Runx family members have both similar and distinct biologic functions.


Assuntos
Fatores de Transcrição/fisiologia , Animais , Células Sanguíneas , Linhagem da Célula , Células Cultivadas , Quimera/crescimento & desenvolvimento , Subunidade alfa 1 de Fator de Ligação ao Core , Subunidade alfa 2 de Fator de Ligação ao Core , Subunidade alfa 3 de Fator de Ligação ao Core , Proteínas de Ligação a DNA , Crescimento e Desenvolvimento , Linfócitos/citologia , Camundongos , Células Mieloides/citologia , Engenharia de Proteínas , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas , Timo/crescimento & desenvolvimento , Fator de Transcrição AP-2 , Fatores de Transcrição/química
4.
Blood ; 103(2): 562-70, 2004 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-14504086

RESUMO

AML1/Runx1 is a frequent target of leukemia-associated gene aberration, and it encodes a transcription factor essential for definitive hematopoiesis. We previously reported that the AML1 molecules with trans-activation subdomains retained can rescue in vitro hematopoietic defects of AML1-deficient mouse embryonic stem (ES) cells when expressed by using a knock-in approach. Extending this notion to in vivo conditions, we found that the knock-in ES cell clones with AML1 mutants, which retain trans-activation subdomains but lack C-terminal repression subdomains including the conserved VWRPY motif, contribute to hematopoietic tissues in chimera mice. We also found that germline mice homozygous for the mutated AML1 allele, which lacks the VWRPY motif, exhibit a minimal effect on hematopoietic development, as was observed in control knock-in mice with full-length AML1. On the other hand, reduced cell numbers and deviant CD4 expression were observed during early T-lymphoid ontogeny in the VWRPY-deficient mice, whereas the contribution to the thymus by the corresponding ES cell clones was inadequate. These findings demonstrate that AML1 with its trans-activating subdomains is essential and sufficient for hematopoietic development in the context of the entire mouse. In addition, its trans-repression activity, depending on the C-terminal VWRPY motif, plays a role in early thymocyte development.


Assuntos
Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Hematopoese/genética , Oligopeptídeos/química , Fatores de Transcrição/genética , Animais , Sequência de Bases , Blastocisto/fisiologia , Sequência Conservada , Subunidade alfa 2 de Fator de Ligação ao Core , Primers do DNA , Éxons/genética , Citometria de Fluxo , Glucose-6-Fosfato Isomerase/genética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Isoenzimas/genética , Fígado/embriologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Gênica/genética
5.
Br J Haematol ; 125(6): 709-19, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15180860

RESUMO

AML1/RUNX1, which encodes a transcription factor essential for definitive haematopoiesis, is a frequent target of leukaemia-associated chromosome translocations. Point mutations of this gene have also recently been associated with leukaemia and myelodysplastic syndrome (MDS). To further define the frequency and biological characteristics of AML1 mutations, we have examined 170 cases of such diseases. Mutations within the runt-domain were identified in five cases: one of de novo acute myeloid leukaemia (AML) and four of MDS. Where multiple time point samples were available, mutations were detected in the earliest samples, which persisted throughout the disease course. Of the five mutations, one was a silent mutation, two were apparent loss-of-function mutations caused by N-terminal truncation, and two were insertions, I150ins and K168ins, which preserved most of the AML1 DNA-binding domain. Both AML1 molecules with insertion mutations were non-functional in that they were unable to rescue haematological defects in AML1-deficient mouse embryonic stem cells. In addition, activating mutations of N-ras, deletion of chromosome 12p, or inactivation of TP53 accompanied some of the AML1 mutations. Together, these observations strongly suggest that one-allele inactivation of AML1 serves as an initial or early event that plays an important role in the eventual development of overt diseases with additional genetic alterations.


Assuntos
Proteínas de Ligação a DNA/genética , Hematopoese/genética , Leucemia Mieloide Aguda/genética , Mutação Puntual , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Subunidade alfa 2 de Fator de Ligação ao Core , Feminino , Inativação Gênica , Engenharia Genética , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Polimorfismo Conformacional de Fita Simples , Células-Tronco/fisiologia
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