Engineered model of t(7;12)(q36;p13) AML recapitulates patient-specific features and gene expression profiles

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 generati...

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Published in:Oncogenesis (New York, NY) NY), 2022-09, Vol.11 (1), p.50-50, Article 50
Main Authors: Ragusa, Denise, Cicirò, Ylenia, Federico, Concetta, Saccone, Salvatore, Bruno, Francesca, Saeedi, Reza, Sisu, Cristina, Pina, Cristina, Sala, Arturo, Tosi, Sabrina
Format: Article
Language:English
Subjects:
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Acute myeloid leukemia
Apoptosis
Brief Communication
CD34 antigen
Cell Biology
CRISPR
Cytogenetics
Gene expression
Human Genetics
Internal Medicine
Leukemia
Medicine
Medicine & Public Health
Molecular modelling
Oncology
Progenitor cells
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Summary: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.
ISSN:2157-9024
2157-9024
DOI:10.1038/s41389-022-00426-2