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Engineered model of t(7;12)(q36;p13) AML recapitulates patient-specific features and gene expression profiles
Denise Ragusa1,2,3, Ylenia Cicirò1,4, Concetta Federico5
1College of Health, Medicine and Life Sciences, Division of Biosciences, Brunel University London, Uxbridge, UB8 3PH, UK.
Insights
Researchers created a new model for infant acute myeloid leukaemia with the t(7;12) translocation. This model helps study the disease
Area of Science:
- Hematology
- Cancer Biology
- Genetics
Background:
- Acute myeloid leukaemia (AML) with the t(7;12) translocation is a rare, high-risk infant cancer.
- This subtype, common in young children, is poorly understood due to limited research models.
- Key features include MNX1 gene overexpression and fusion transcripts in some patients.
Purpose of the Study:
- To engineer a novel, clinically relevant in vitro model for t(7;12) AML.
- To investigate the biological consequences of the t(7;12) translocation.
- To facilitate the study of molecular mechanisms driving this specific AML subtype.
Main Methods:
- CRISPR/Cas9 gene editing was used to introduce the t(7;12) translocation into K562 cells and primary hematopoietic progenitors.
- Cellular behavior was assessed using clonogenic assays and serial replating.
- Nuclear localization of the MNX1 locus and transcriptional profiles were analyzed.
Main Results:
- The t(7;12) translocation was successfully established and maintained in the K562 cell line, unlike in primary progenitors.
- K562-t(7;12) cells showed sustained myeloid bias and altered MNX1 nuclear localization.
- The engineered model accurately reflected the transcriptional landscape of patient-derived t(7;12) AML.
Conclusions:
- A functional K562 cell line model for t(7;12) AML has been developed.
- This model recapitulates key molecular and cellular features of the disease.
- It offers a valuable platform for exploring therapeutic targets and understanding disease pathogenesis.
Abstract:
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.
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