Similar Datasets
Project description:Acute myeloid leukemia (AML) with translocation t(7;12)(q36;p13) is a subgroup that occurs only in infants or very young children and is characterised by a poor outcome. Deep molecular characterization has been hampered by the rarity of this AML subtype and the lack of model systems. Approximately 50% of AML with t(7;12)(q36;p13) express an MNX1::ETV6 oncofusion transcript, but there is no evidence for the presence of an oncofusion protein. However, a universal feature is the strong RNA and protein expression of MNX1, a homeobox transcription factor that is normally not transcribed in haematopoietic cells. Here we use whole genome sequencing data to precisely map the translocation breakpoints on chromosomes 7 and 12 in these pediatric AML patients to a region downstream of MNX1 on chromosome 7 and either introns 1 or 2 of ETV6 on chromosome 12. We confirm the tight correlation of MNX1 overexpression in t(7;12)(q36;p13) AML in our own samples and three additional cohorts of pediatric AML. Using a CRISPR-engineered iPSC cell line, ChiPSC22t(7;12), harbouring the t(7;12)(q36;p13) translocation, we unravel an enhancer-hijacking event leading to MNX1 overexpression. Identification of hematopoietic enhancer regions in hematopoietic stem and progenitor cells derived from differentiated ChiPSC22t(7;12) cells allowed us to demonstrate their importance for MNX1 expression in knock-out experiments and by measuring the promoter-enhancer distance in confocal microscopy. In contrast to the prevailing dogma in AML, suggesting that translocations lead to the creation of oncofusion genes, t(7;12)(q36;p13) AML is characterized by an enhancer-hijacking event driving MNX1, a novel leukemia oncogene and the haploinsufficiency of ETV6.
2024-08-21 | GSE244277 | GEO
Project description:Acute myeloid leukemia (AML) with translocation t(7;12)(q36;p13) is a subgroup that occurs only in infants or very young children and is characterised by a poor outcome. Deep molecular characterization has been hampered by the rarity of this AML subtype and the lack of model systems. Approximately 50% of AML with t(7;12)(q36;p13) express an MNX1::ETV6 oncofusion transcript, but there is no evidence for the presence of an oncofusion protein. However, a universal feature is the strong RNA and protein expression of MNX1, a homeobox transcription factor that is normally not transcribed in haematopoietic cells. Here we use whole genome sequencing data to precisely map the translocation breakpoints on chromosomes 7 and 12 in these pediatric AML patients to a region downstream of MNX1 on chromosome 7 and either introns 1 or 2 of ETV6 on chromosome 12. We confirm the tight correlation of MNX1 overexpression in t(7;12)(q36;p13) AML in our own samples and three additional cohorts of pediatric AML. Using a CRISPR-engineered iPSC cell line, ChiPSC22t(7;12), harbouring the t(7;12)(q36;p13) translocation, we unravel an enhancer-hijacking event leading to MNX1 overexpression. Identification of hematopoietic enhancer regions in hematopoietic stem and progenitor cells derived from differentiated ChiPSC22t(7;12) cells allowed us to demonstrate their importance for MNX1 expression in knock-out experiments and by measuring the promoter-enhancer distance in confocal microscopy. In contrast to the prevailing dogma in AML, suggesting that translocations lead to the creation of oncofusion genes, t(7;12)(q36;p13) AML is characterized by an enhancer-hijacking event driving MNX1, a novel leukemia oncogene and the haploinsufficiency of ETV6.
2024-08-21 | GSE244275 | GEO
Project description:Acute myeloid leukemia (AML) with translocation t(7;12)(q36;p13) is a subgroup that occurs only in infants or very young children and is characterised by a poor outcome. Deep molecular characterization has been hampered by the rarity of this AML subtype and the lack of model systems. Approximately 50% of AML with t(7;12)(q36;p13) express an MNX1::ETV6 oncofusion transcript, but there is no evidence for the presence of an oncofusion protein. However, a universal feature is the strong RNA and protein expression of MNX1, a homeobox transcription factor that is normally not transcribed in haematopoietic cells. Here we use whole genome sequencing data to precisely map the translocation breakpoints on chromosomes 7 and 12 in these pediatric AML patients to a region downstream of MNX1 on chromosome 7 and either introns 1 or 2 of ETV6 on chromosome 12. We confirm the tight correlation of MNX1 overexpression in t(7;12)(q36;p13) AML in our own samples and three additional cohorts of pediatric AML. Using a CRISPR-engineered iPSC cell line, ChiPSC22t(7;12), harbouring the t(7;12)(q36;p13) translocation, we unravel an enhancer-hijacking event leading to MNX1 overexpression. Identification of hematopoietic enhancer regions in hematopoietic stem and progenitor cells derived from differentiated ChiPSC22t(7;12) cells allowed us to demonstrate their importance for MNX1 expression in knock-out experiments and by measuring the promoter-enhancer distance in confocal microscopy. In contrast to the prevailing dogma in AML, suggesting that translocations lead to the creation of oncofusion genes, t(7;12)(q36;p13) AML is characterized by an enhancer-hijacking event driving MNX1, a novel leukemia oncogene and the haploinsufficiency of ETV6.
2024-08-21 | GSE244274 | GEO
Project description:Acute myeloid leukemia (AML) with translocation t(7;12)(q36;p13) is a subgroup that occurs only in infants or very young children and is characterised by a poor outcome. Deep molecular characterization has been hampered by the rarity of this AML subtype and the lack of model systems. Approximately 50% of AML with t(7;12)(q36;p13) express an MNX1::ETV6 oncofusion transcript, but there is no evidence for the presence of an oncofusion protein. However, a universal feature is the strong RNA and protein expression of MNX1, a homeobox transcription factor that is normally not transcribed in haematopoietic cells. Here we use whole genome sequencing data to precisely map the translocation breakpoints on chromosomes 7 and 12 in these pediatric AML patients to a region downstream of MNX1 on chromosome 7 and either introns 1 or 2 of ETV6 on chromosome 12. We confirm the tight correlation of MNX1 overexpression in t(7;12)(q36;p13) AML in our own samples and three additional cohorts of pediatric AML. Using a CRISPR-engineered iPSC cell line, ChiPSC22t(7;12), harbouring the t(7;12)(q36;p13) translocation, we unravel an enhancer-hijacking event leading to MNX1 overexpression. Identification of hematopoietic enhancer regions in hematopoietic stem and progenitor cells derived from differentiated ChiPSC22t(7;12) cells allowed us to demonstrate their importance for MNX1 expression in knock-out experiments and by measuring the promoter-enhancer distance in confocal microscopy. In contrast to the prevailing dogma in AML, suggesting that translocations lead to the creation of oncofusion genes, t(7;12)(q36;p13) AML is characterized by an enhancer-hijacking event driving MNX1, a novel leukemia oncogene and the haploinsufficiency of ETV6.
2024-08-21 | GSE244446 | GEO
Project description:Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7 12)(q36 p13)
| PRJNA1022491 | ENA
Project description:Acute myeloid leukaemia carrying the translocation t(7;12)(q36;p13) is an adverse-risk leukaemia uniquely observed in infants. Despite constituting up to 30% of cases in under 2-year-olds, it remains poorly understood. Known molecular features are ectopic overexpression of the MNX1 gene and generation of a fusion transcript in 50% of patients. Lack of research models has hindered understanding of t(7;12) biology, which has historically focused on MNX1 overexpression rather than the cytogenetic entity itself. Here, we employed CRISPR/Cas9 to generate t(7;12) in the human K562 cell line, and in healthy CD34+ haematopoietic progenitors where the translocation was not sustained in long-term cultures or through serial replating. In contrast, in K562 cells, t(7;12) was propagated in self-renewing clonogenic assays, with sustained myeloid bias in colony formation and baseline depletion of erythroid signatures. Nuclear localisation analysis revealed repositioning of the translocated MNX1 locus to the interior of t(7;12)-harbouring K562 nuclei - a known phenomenon in t(7;12) patients which associates with ectopic overexpression of MNX1. Crucially, the K562-t(7;12) model successfully recapitulated the transcriptional landscape of t(7;12) patient leukaemia. In summary, we engineered a clinically-relevant model of t(7;12) acute myeloid leukaemia with the potential to unravel targetable molecular mechanisms of disease.
| S-EPMC9440899 | biostudies-literature
Project description:Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7 12)(q36 p13) [4C-Seq]
| PRJNA1022053 | ENA
Project description:Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7 12)(q36 p13) [ATAC-Seq]
| PRJNA1022052 | ENA
Project description:Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7 12)(q36 p13) [ACT-Seq]
| PRJNA1023180 | ENA
Project description:We recreated the t(7;12) translocation in K562 cells by CRISPR/Cas9 to understand its effects on haematopoietic cells, which is of relevance to understand how this cytogenetic abnormalities causes and promotes acute leukaemia in infants. Wild-type K562 were edited by electroporation of ribonucleoprotein complexes consisting of Cas9 enzyme and two guide RNAs targeting patient-specific breakpoint loci. K562 electroporated with Cas9 enzyme only were used as control. Edited K562 harbouring the t(7;12) were single-cell cloned to obtain homogeneous populations (hereby referred to as K562-t(7;12)). We performed RNA sequencing analysis of K562-t(7;12) compared to K562 control to uncover transcriptional changes associated with the translocation.
2022-09-06 | E-MTAB-11851 | biostudies-arrayexpress