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1.
Blood ; 136(6): 698-714, 2020 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-32350520

RESUMEN

Acute erythroleukemia (AEL or acute myeloid leukemia [AML]-M6) is a rare but aggressive hematologic malignancy. Previous studies showed that AEL leukemic cells often carry complex karyotypes and mutations in known AML-associated oncogenes. To better define the underlying molecular mechanisms driving the erythroid phenotype, we studied a series of 33 AEL samples representing 3 genetic AEL subgroups including TP53-mutated, epigenetic regulator-mutated (eg, DNMT3A, TET2, or IDH2), and undefined cases with low mutational burden. We established an erythroid vs myeloid transcriptome-based space in which, independently of the molecular subgroup, the majority of the AEL samples exhibited a unique mapping different from both non-M6 AML and myelodysplastic syndrome samples. Notably, >25% of AEL patients, including in the genetically undefined subgroup, showed aberrant expression of key transcriptional regulators, including SKI, ERG, and ETO2. Ectopic expression of these factors in murine erythroid progenitors blocked in vitro erythroid differentiation and led to immortalization associated with decreased chromatin accessibility at GATA1-binding sites and functional interference with GATA1 activity. In vivo models showed development of lethal erythroid, mixed erythroid/myeloid, or other malignancies depending on the cell population in which AEL-associated alterations were expressed. Collectively, our data indicate that AEL is a molecularly heterogeneous disease with an erythroid identity that results in part from the aberrant activity of key erythroid transcription factors in hematopoietic stem or progenitor cells.


Asunto(s)
Leucemia Eritroblástica Aguda/genética , Proteínas de Neoplasias/fisiología , Factores de Transcripción/fisiología , Transcriptoma , Adulto , Animales , Transformación Celular Neoplásica/genética , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/fisiología , Dioxigenasas , Eritroblastos/metabolismo , Eritropoyesis/genética , Femenino , Factor de Transcripción GATA1/deficiencia , Factor de Transcripción GATA1/genética , Técnicas de Sustitución del Gen , Heterogeneidad Genética , Células Madre Hematopoyéticas/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Transgénicos , Persona de Mediana Edad , Mutación , Proteínas de Neoplasias/genética , Células Madre Neoplásicas/metabolismo , Proteínas Proto-Oncogénicas/deficiencia , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/fisiología , RNA-Seq , Quimera por Radiación , Proteínas Represoras/genética , Proteínas Represoras/fisiología , Factores de Transcripción/genética , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/fisiología , Secuenciación del Exoma , Adulto Joven
2.
J Cell Mol Med ; 21(6): 1237-1242, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-27997762

RESUMEN

Familial platelet disorder with predisposition to acute myeloid leukaemia (FPD/AML) is characterized by germline RUNX1 mutations, thrombocytopaenia, platelet dysfunction and a risk of developing acute myeloid and in rare cases lymphoid T leukaemia. Here, we focus on a case of a man with a familial history of RUNX1R174Q mutation who developed at the age of 42 years a T2-ALL and, 2 years after remission, an AML-M0. Both AML-M0 and T2-ALL blast populations demonstrated a loss of 1p36.32-23 and 17q11.2 regions as well as other small deletions, clonal rearrangements of both TCRγ and TCRδ and a presence of 18 variants at a frequency of more than 40%. Additional variants were identified only in T2-ALL or in AML-M0 evoking the existence of a common original clone, which gave rise to subclonal populations. Next generation sequencing (NGS) performed on peripheral blood-derived CD34+ cells 5 years prior to T2-ALL development revealed only the missense TET2P1962T mutation at a frequency of 1%, which increases to more than 40% in fully transformed leukaemic T2-ALL and AML-M0 clones. This result suggests that TET2P1962T mutation in association with germline RUNX1R174Q mutation leads to amplification of a haematopoietic clone susceptible to acquire other transforming alterations.


Asunto(s)
Trastornos de las Plaquetas Sanguíneas/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteínas de Unión al ADN/genética , Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogénicas/genética , Adulto , Antígenos CD34/genética , Trastornos de las Plaquetas Sanguíneas/complicaciones , Trastornos de las Plaquetas Sanguíneas/patología , Plaquetas/patología , Dioxigenasas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/patología , Masculino
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