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1.
BMJ Case Rep ; 13(12)2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33370941

RESUMO

A 9-year-old girl was admitted to the paediatric intensive care unit with acute respiratory failure due to influenza. Nine months earlier, she presented with unexplained lymphoedema of the lower extremities and monocytopenia. She had a history of occasional finger warts and onychomycoses. During hospitalisation, the patient was diagnosed with Emberger syndrome caused by GATA2 deficiency. The admission was complicated by thromboses in the right hand, leading to amputation of multiple fingers. From then on, the patient has been in good recovery, the function of her right hand was improving and an allogeneic haematopoietic cell transplantation has now been successfully performed.


Assuntos
Dedos/patologia , Deficiência de GATA2/complicações , Fator de Transcrição GATA2/deficiência , Vírus da Influenza A/imunologia , /imunologia , Amputação , Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Criança , Códon sem Sentido , Análise Mutacional de DNA , Quimioterapia Combinada , Feminino , Dedos/cirurgia , Deficiência de GATA2/diagnóstico , Deficiência de GATA2/genética , Deficiência de GATA2/imunologia , Fator de Transcrição GATA2/genética , Gangrena/imunologia , Gangrena/cirurgia , Glucocorticoides/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Vírus da Influenza A/isolamento & purificação , Influenza Humana/complicações , Influenza Humana/imunologia , Influenza Humana/terapia , Influenza Humana/virologia , Pulmão/diagnóstico por imagem , Pulmão/imunologia , Respiração Artificial , /terapia , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X
2.
Leukemia ; 34(10): 2673-2687, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32555368

RESUMO

Deficiency of the transcription factor GATA2 is a highly penetrant genetic disorder predisposing to myelodysplastic syndromes (MDS) and immunodeficiency. It has been recognized as the most common cause underlying primary MDS in children. Triggered by the discovery of a recurrent synonymous GATA2 variant, we systematically investigated 911 patients with phenotype of pediatric MDS or cellular deficiencies for the presence of synonymous alterations in GATA2. In total, we identified nine individuals with five heterozygous synonymous mutations: c.351C>G, p.T117T (N = 4); c.649C>T, p.L217L; c.981G>A, p.G327G; c.1023C>T, p.A341A; and c.1416G>A, p.P472P (N = 2). They accounted for 8.2% (9/110) of cases with GATA2 deficiency in our cohort and resulted in selective loss of mutant RNA. While for the hotspot mutation (c.351C>G) a splicing error leading to RNA and protein reduction was identified, severe, likely late stage RNA loss without splicing disruption was found for other mutations. Finally, the synonymous mutations did not alter protein function or stability. In summary, synonymous GATA2 substitutions are a new common cause of GATA2 deficiency. These findings have broad implications for genetic counseling and pathogenic variant discovery in Mendelian disorders.


Assuntos
Deficiência de GATA2/genética , Fator de Transcrição GATA2/deficiência , Fator de Transcrição GATA2/genética , RNA/genética , Mutação Silenciosa/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Heterozigoto , Humanos , Síndromes de Imunodeficiência/genética , Masculino , Síndromes Mielodisplásicas/genética , Fenótipo , Adulto Jovem
3.
Leukemia ; 34(3): 759-770, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31624376

RESUMO

Inversion of chromosome 16 (inv(16)) generates a fusion gene CBFB-MYH11, which is a driver mutation for acute myeloid leukemia (AML). Gene expression profiling suggests that Gata2, a hematopoietic transcription factor, is a top upregulated gene in preleukemic Cbfb-MYH11 knockin mice and is expressed in human inv(16) AML. On the other hand, we have also identified recurrent monoallelic deletions of GATA2 in relapsed human CBF-AML patients. To clarify the role of Gata2 in leukemogenesis by Cbfb-MYH11, we generated conditional Cbfb-MYH11 knockin mice with Gata2 heterozygous knockout. Gata2 heterozygous knockout reduced abnormal myeloid progenitors, which are capable of inducing leukemia in the Cbfb-MYH11 mice. Consequently, Cbfb-MYH11 mice with Gata2 heterozygous knockout developed leukemia with longer latencies than those with intact Gata2. Interestingly, leukemic cells with Gata2 heterozygous knockout gained higher number of mutations and showed more aggressive phenotype in both primary and transplanted mice. Moreover, leukemic cells with Gata2 heterozygous knockout showed higher repopulating capacity in competitive transplantation experiments. In summary, reduction of Gata2 activity affects mutational dynamics of leukemia with delayed leukemia onset in Cbfb-MYH11 knockin mice, but paradoxically results in a more aggressive leukemia phenotype, which may be correlated with leukemia relapse or poor prognosis in human patients.


Assuntos
Carcinogênese/genética , Subunidade beta de Fator de Ligação ao Core/genética , Deficiência de GATA2/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/genética , Cadeias Pesadas de Miosina/genética , Animais , Inversão Cromossômica , Cromossomos Humanos Par 16 , Feminino , Heterozigoto , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Proteínas de Fusão Oncogênica/genética , Fenótipo
5.
BMC Med Genet ; 20(1): 64, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035956

RESUMO

BACKGROUND: GATA2 is a transcription factor that is a critical regulator of gene expression in hematopoietic cells. GATA2 deficiency presents with multi-lineage cytopenia, mycobacterial, fungal and viral infections. Patients with GATA2 mutation have a high risk of developing myelodysplastic syndrome or acute myeloid leukemia. CASE PRESENTATION: We described a 43 years-old white male with 20-year follow-up of autoimmune and thrombotic phenomena, hypothyroidism, disseminated refractory Mycobacterium kansasii infection and MonoMAC syndrome. GATA2 c.1061 C > T; p.T354 M mutation was identified after he progressed from myelodysplastic pancytopenia to refractory anemia with excess blasts type II. His relatives were also investigated and he underwent unsuccessful haematopoietic stem cell transplantation. We discuss the clinical features, genetic diagnosis and treatment of this immunodeficiency disorder. CONCLUSIONS: This case illustrates the challenge how a multidisciplinary disease should be handle. Once usual causes of immunodeficiency were excluded, clinicians should considerGATA2 deficiency in patients with myelodysplasia and long-standing Mycobacterium kansasii infection.


Assuntos
Deficiência de GATA2/genética , Fator de Transcrição GATA2/genética , Mutação , Infecções por Mycobacterium não Tuberculosas/genética , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium kansasii/isolamento & purificação , Síndromes Mielodisplásicas/genética , Adulto , Antibacterianos/uso terapêutico , Humanos , Masculino , Infecções por Mycobacterium não Tuberculosas/complicações , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico
8.
J Clin Invest ; 129(3): 1180-1192, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30620726

RESUMO

The development and function of stem and progenitor cells that produce blood cells are vital in physiology. GATA-binding protein 2 (GATA2) mutations cause GATA-2 deficiency syndrome involving immunodeficiency, myelodysplastic syndrome, and acute myeloid leukemia. GATA-2 physiological activities necessitate that it be strictly regulated, and cell type-specific enhancers fulfill this role. The +9.5 intronic enhancer harbors multiple conserved cis-elements, and germline mutations of these cis-elements are pathogenic in humans. Since mechanisms underlying how GATA2 enhancer disease mutations impact hematopoiesis and pathology are unclear, we generated mouse models of the enhancer mutations. While a multi-motif mutant was embryonically lethal, a single-nucleotide Ets motif mutant was viable, and steady-state hematopoiesis was normal. However, the Ets motif mutation abrogated stem/progenitor cell regeneration following stress. These results reveal a new mechanism in human genetics, in which a disease predisposition mutation inactivates enhancer regenerative activity, while sparing developmental activity. Mutational sensitization to stress that instigates hematopoietic failure constitutes a paradigm for GATA-2 deficiency syndrome and other contexts of GATA-2-dependent pathogenesis.


Assuntos
Elementos Facilitadores Genéticos , Deficiência de GATA2 , Fator de Transcrição GATA2 , Mutação em Linhagem Germinativa , Hematopoese/genética , Motivos de Nucleotídeos , Regeneração/genética , Animais , Deficiência de GATA2/genética , Deficiência de GATA2/metabolismo , Fator de Transcrição GATA2/genética , Fator de Transcrição GATA2/metabolismo , Humanos , Camundongos , Camundongos Mutantes
10.
Blood Adv ; 2(23): 3553-3565, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30538114

RESUMO

GATA2 deficiency is an inherited or sporadic genetic disorder characterized by distinct cellular deficiency, bone marrow failure, various infections, lymphedema, pulmonary alveolar proteinosis, and predisposition to myeloid malignancies resulting from heterozygous loss-of-function mutations in the GATA2 gene. How heterozygous GATA2 mutations affect human hematopoietic development or cause characteristic cellular deficiency and eventual hypoplastic myelodysplastic syndrome or leukemia is not fully understood. We used induced pluripotent stem cells (iPSCs) to study hematopoietic development in the setting of GATA2 deficiency. We performed hematopoietic differentiation using iPSC derived from patients with GATA2 deficiency and examined their ability to commit to mesoderm, hemogenic endothelial precursors (HEPs), hematopoietic stem progenitor cells, and natural killer (NK) cells. Patient-derived iPSC, either derived from fibroblasts/marrow stromal cells or peripheral blood mononuclear cells, did not show significant defects in committing to mesoderm, HEP, hematopoietic stem progenitor, or NK cells. However, HEP derived from GATA2-mutant iPSC showed impaired maturation toward hematopoietic lineages. Hematopoietic differentiation was nearly abolished from homozygous GATA2 knockout (KO) iPSC lines and markedly reduced in heterozygous KO lines compared with isogenic controls. On the other hand, correction of the mutated GATA2 allele in patient-specific iPSC did not alter hematopoietic development consistently in our model. GATA2 deficiency usually manifests within the first decade of life. Newborn and infant hematopoiesis appears to be grossly intact; therefore, our iPSC model indeed may resemble the disease phenotype, suggesting that other genetic, epigenetic, or environmental factors may contribute to bone marrow failure in these patients following birth. However, heterogeneity of PSC-based models and limitations of in vitro differentiation protocol may limit the possibility to detect subtle cellular phenotypes.


Assuntos
Deficiência de GATA2/patologia , Fator de Transcrição GATA2/genética , Hematopoese , Células-Tronco Pluripotentes Induzidas/metabolismo , Adulto , Antígenos CD34/metabolismo , Diferenciação Celular , Feminino , Deficiência de GATA2/genética , Edição de Genes , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Heterozigoto , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Antígenos Comuns de Leucócito/metabolismo , Masculino , Mesoderma/citologia , Mesoderma/metabolismo , Pessoa de Meia-Idade , Mutação
11.
Obstet Gynecol ; 132(5): 1112-1115, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30303925

RESUMO

BACKGROUND: Vulvar cancer has become more prevalent, and its causes include chronic dermatoses and human papillomavirus (HPV)-mediated disease. Younger immunocompromised women can also be affected. We describe a case of vulvar carcinoma as a result of GATA2 deficiency. CASE: A 19-year-old woman presented to our gynecologic oncology clinic for management of a large vulvar mass. She was diagnosed with stage IB vulvar carcinoma after vulvectomy. GATA2 deficiency was the contributing factor causing vulvar carcinoma. CONCLUSION: GATA2 deficiency causes immunodeficiency in young women, and patients with early-onset HPV-related disease, a family or personal history of leukemia, recurrent infection, or immune irregularities should be screened. Health care providers for these women are often obstetrician-gynecologists, who can provide diagnosis, treatment, referral, and prevention of HPV-related diseases.


Assuntos
Carcinoma in Situ/etiologia , Carcinoma de Células Escamosas/etiologia , Condiloma Acuminado/etiologia , Deficiência de GATA2/complicações , Síndromes de Imunodeficiência/complicações , Recidiva Local de Neoplasia/cirurgia , Neoplasias Vulvares/etiologia , Carcinoma in Situ/cirurgia , Carcinoma de Células Escamosas/cirurgia , Condiloma Acuminado/cirurgia , Feminino , Deficiência de GATA2/genética , Humanos , Síndromes de Imunodeficiência/genética , Neoplasias Vulvares/cirurgia , Adulto Jovem
13.
Hematol Oncol Clin North Am ; 32(4): 713-728, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30047422

RESUMO

GATA2 deficiency is an immunodeficiency and bone marrow failure disorder caused by pathogenic variants in GATA2. It is inherited in an autosomal-dominant pattern or can be due to de novo sporadic germline mutation. Patients commonly have B-cell, dendritic cell, natural killer cell, and monocytopenias, and are predisposed to myelodysplastic syndrome, acute myeloid leukemia, and chronic myelomonocytic leukemia. Patients may suffer from disseminated human papilloma virus and mycobacterial infections, pulmonary alveolar proteinosis, and lymphedema. The bone marrow eventually takes on a characteristic hypocellular myelodysplasia with loss of monocytes and hematogones, megakaryocytes with separated nuclear lobes, micromegakaryocytes, and megakaryocytes with hypolobated nuclei.


Assuntos
Anemia Aplástica , Doenças da Medula Óssea , Deficiência de GATA2 , Fator de Transcrição GATA2/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Hemoglobinúria Paroxística , Anemia Aplástica/genética , Anemia Aplástica/metabolismo , Anemia Aplástica/patologia , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/metabolismo , Doenças da Medula Óssea/patologia , Transtornos da Insuficiência da Medula Óssea , Deficiência de GATA2/genética , Deficiência de GATA2/metabolismo , Deficiência de GATA2/patologia , Hemoglobinúria Paroxística/genética , Hemoglobinúria Paroxística/metabolismo , Hemoglobinúria Paroxística/patologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia
14.
J Clin Immunol ; 38(4): 513-526, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29882021

RESUMO

The pathogenesis of life-threatening influenza A virus (IAV) disease remains elusive, as infection is benign in most individuals. We studied two relatives who died from influenza. We Sanger sequenced GATA2 and evaluated the mutation by gene transfer, measured serum cytokine levels, and analyzed circulating T- and B-cells. Both patients (father and son, P1 and P2) died in 2011 of H1N1pdm IAV infection at the ages of 54 and 31 years, respectively. They had not suffered from severe or moderately severe infections in the last 17 (P1) and 15 years (P2). A daughter of P1 had died at 20 years from infectious complications. Low B-cell, NK- cell, and monocyte numbers and myelodysplastic syndrome led to sequence GATA2. Patients were heterozygous for a novel, hypomorphic, R396L mutation leading to haplo-insufficiency. B- and T-cell rearrangement in peripheral blood from P1 during the influenza episode showed expansion of one major clone. No T-cell receptor excision circles were detected in P1 and P3 since they were 35 and 18 years, respectively. Both patients presented an exuberant, interferon (IFN)-γ-mediated hypercytokinemia during H1N1pdm infection. No data about patients with viremia was available. Two previously reported adult GATA2-deficient patients died from severe H1N1 IAV infection; GATA2 deficiency may predispose to life-threatening influenza in adulthood. However, a role of other genetic variants involved in immune responses cannot be ruled out. Patients with GATA2 deficiency can reach young adulthood without severe infections, including influenza, despite long-lasting complete B-cell and natural killer (NK) cell deficiency, as well as profoundly diminished T-cell thymic output.


Assuntos
Deficiência de GATA2/complicações , Influenza Humana/diagnóstico , Influenza Humana/etiologia , Biomarcadores , Citocinas/sangue , Análise Mutacional de DNA , Evolução Fatal , Feminino , Deficiência de GATA2/diagnóstico , Deficiência de GATA2/genética , Fator de Transcrição GATA2/genética , Humanos , Imunofenotipagem , Vírus da Influenza A , Influenza Humana/virologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Mutação , Linhagem
15.
Haematologica ; 103(8): 1278-1287, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29724903

RESUMO

Heterozygous germline GATA2 mutations strongly predispose to leukemia, immunodeficiency, and/or lymphoedema. We describe a series of 79 patients (53 families) diagnosed since 2011, made up of all patients in France and Belgium, with a follow up of 2249 patients/years. Median age at first clinical symptoms was 18.6 years (range, 0-61 years). Severe infectious diseases (mycobacteria, fungus, and human papilloma virus) and hematologic malignancies were the most common first manifestations. The probability of remaining symptom-free was 8% at 40 years old. Among the 53 probands, 24 had missense mutations including 4 recurrent alleles, 21 had nonsense or frameshift mutations, 4 had a whole-gene deletion, 2 had splice defects, and 2 patients had complex mutations. There were significantly more cases of leukemia in patients with missense mutations (n=14 of 34) than in patients with nonsense or frameshift mutations (n=2 of 28). We also identify new features of the disease: acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, fatal progressive multifocal leukoencephalopathy related to the JC virus, and immune/inflammatory diseases. A revised International Prognostic Scoring System (IPSS) score allowed a distinction to be made between a stable disease and hematologic transformation. Chemotherapy is of limited efficacy, and has a high toxicity with severe infectious complications. As the mortality rate is high in our cohort (up to 35% at the age of 40), hematopoietic stem cell transplantation (HSCT) remains the best choice of treatment to avoid severe infectious and/or hematologic complications. The timing of HSCT remains difficult to determine, but the earlier it is performed, the better the outcome.


Assuntos
Deficiência de GATA2/epidemiologia , Mutação em Linhagem Germinativa , Adulto Jovem , Adolescente , Adulto , Bélgica , Criança , Pré-Escolar , França , Deficiência de GATA2/complicações , Deficiência de GATA2/genética , Deficiência de GATA2/terapia , Neoplasias Hematológicas/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Recém-Nascido , Infecções/etiologia , Pessoa de Meia-Idade , Mortalidade , Prognóstico , Inquéritos e Questionários
16.
J Pediatr Hematol Oncol ; 40(4): e225-e228, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29620682

RESUMO

GATA2 deficiency is an inherited bone marrow failure syndrome that can manifest with myelodysplasia (myelodysplastic syndrome) with chromosomal aberrations and high risk of evolution to leukemia (particularly, acute myeloid leukemia); immunodeficiency with opportunistic infections; and/or lymphedema. It can be transmitted in families in autosomal-dominant fashion, or present de novo as sporadic disease in adults or children. The authors report a case of an adolescent male with features of GATA2 deficiency resulting from a complete monoallelic deletion, review chromosomal anomalies associated with this disorder, and discuss the management implications.


Assuntos
Aberrações Cromossômicas , Deficiência de GATA2/genética , Fator de Transcrição GATA2/genética , Deleção de Genes , Síndromes Mielodisplásicas/genética , Adolescente , Deficiência de GATA2/patologia , Humanos , Masculino , Síndromes Mielodisplásicas/patologia
17.
Mol Cell Biol ; 38(12)2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29581184

RESUMO

The transcription factor GATA2 is required for expansion and differentiation of hematopoietic stem cells (HSCs). In mesenchymal stem cells (MSCs), GATA2 blocks adipogenesis, but its biological relevance and underlying genomic events are unknown. We report a dual function of GATA2 in bone homeostasis. GATA2 in MSCs binds near genes involved in skeletal system development and colocalizes with motifs for FOX and HOX transcription factors, known regulators of skeletal development. Ectopic GATA2 blocks osteoblastogenesis by interfering with SMAD1/5/8 activation. MSC-specific deletion of GATA2 in mice increases the numbers and differentiation capacity of bone-derived precursors, resulting in elevated bone formation. Surprisingly, MSC-specific GATA2 deficiency impairs the trabecularization and mechanical strength of bone, involving reduced MSC expression of the osteoclast inhibitor osteoprotegerin and increased osteoclast numbers. Thus, GATA2 affects bone turnover via MSC-autonomous and indirect effects. By regulating bone trabecularization, GATA2 expression in the osteogenic lineage may contribute to the anatomical and cellular microenvironment of the HSC niche required for hematopoiesis.


Assuntos
Osso e Ossos/metabolismo , Fator de Transcrição GATA2/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Mesenquimais/citologia , Osteogênese/genética , Células 3T3 , Animais , Sítios de Ligação/genética , Células da Medula Óssea/metabolismo , Diferenciação Celular/genética , Linhagem Celular , Microambiente Celular/genética , Fraturas Ósseas/genética , Deficiência de GATA2/genética , Deficiência de GATA2/patologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Proteínas Nucleares/metabolismo , Proteína Smad1/metabolismo , Proteína Smad5/metabolismo , Proteína Smad8/metabolismo , Fatores de Transcrição/metabolismo
18.
Nat Rev Clin Oncol ; 15(4): 219-233, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29311715

RESUMO

Several haematological malignancies, including multiple myeloma (MM) and acute myeloid leukaemia (AML), have well-defined precursor states that precede the development of overt cancer. MM is almost always preceded by monoclonal gammopathy of undetermined significance (MGUS), and at least a quarter of all patients with myelodysplastic syndromes (MDS) have disease that evolves into AML. In turn, MDS are frequently anteceded by clonal haematopoiesis of indeterminate potential (CHIP). The acquisition of additional genetic and epigenetic alterations over time clearly influences the increasingly unstable and aggressive behaviour of neoplastic haematopoietic clones; however, perturbations in the bone-marrow microenvironment are increasingly recognized to have key roles in initiating and supporting oncogenesis. In this Review, we focus on the concept that the haematopoietic neoplasia-microenvironment relationship is an intimate rapport between two partners, provide an overview of the evidence supporting a role for the bone-marrow niche in promoting neoplasia, and discuss the potential for niche-specific therapeutic targets.


Assuntos
Deficiência de GATA2/genética , Leucemia Mieloide Aguda/genética , Gamopatia Monoclonal de Significância Indeterminada/genética , Mieloma Múltiplo/genética , Células da Medula Óssea/patologia , Evolução Clonal/genética , Deficiência de GATA2/patologia , Hematopoese/genética , Humanos , Leucemia Mieloide Aguda/patologia , Gamopatia Monoclonal de Significância Indeterminada/patologia , Mieloma Múltiplo/patologia , Células-Tronco Neoplásicas/patologia , Nicho de Células-Tronco/genética , Microambiente Tumoral/genética
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