Rhea Desai, Sarvenaz Taghavi, Jessica Chase, Martin Chopra, Jenny Chien, Peter Browett, Purvi Kakadia and Stefan Bohlander from the Leukaemia and Blood Cancer Research Unit published a paper in the journal ‘Leukemia’, a Nature publishing group journal and the #2 journal in the field of haematology. The paper is entitled ‘Unexpected variation in leukemia stem cell frequency and genetic heterogeneity in two murine leukemia models initiated by AML1/ETO9a and CALM/AF10’.
Acute myeloid leukemia (AML) is an extremely aggressive, genetically heterogeneous disorder requiring the acquisition of multiple (two to eight) genetic aberrations which act in concert and result in the malignant transformation of a hematopoietic cell. Advances in molecular techniques, particularly the advent of next generation sequencing, has led to the identification of a plethora of genetic lesions and greatly increased our understanding of the molecular heterogeneity of AML.
However, In vivo modeling of the genetic heterogeneity observed in human leukemia remains a major challenge. To address this, the group established murine bone marrow transplantation leukemia models using two primary driver oncogenes – AML1/ETO9a (A/E9a), an alternatively spliced isoform of AML1/ETO and CALM/AF10 minimal fusion (C/A-MF), which contains the regions of CALM/AF10 required for leukemogenesis. They found that the A/E9a and C/A-MF primary transplanted mice developed leukemia with complete penetrance. Whole exome sequencing of the leukemias revealed somatic mutations in genes that are often mutated in patient samples (e.g.: Flt3, Kras, Ptpn11, Bcor).
Analysis of the leukemic transcriptome showed a strong driver oncogene associated signature. In addition, limiting dilution transplantation assays were performed and it was unexpectedly found that leukemias initiated by the same fusion varied in their leukemia stem cell frequencies (between 1:229 to 1:21 707). The models established in the study recapitulate several characteristics of human leukemias and also reveal that leukemia models, even when driven by the same fusion gene, are quite diverse. These immune-competent models provide a unique resource to elucidate molecular mechanisms of leukemogenesis and to develop and test novel therapeutic strategies.
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