To identify a metabolic inhibitor for EVI1-induced metabolic reprogramming in MLL-r AML, we used an XFp extracellular flux analyzer to examine metabolic changes during leukemia development in mouse models of AML expressing MLL-AF9 and Evi1 (Evi1/MF9).
However, aberrantly high expression of EVI1 has potent oncogenic properties and confers poor prognosis and chemo-resistance in leukemia and solid tumors.
We demonstrate for the first time that EVI1 acts as a regulator of its own expression, highlighting the complex regulation of EVI1, and open new directions to better understand the mechanisms of EVI1 overexpressing leukemias.
Genetic deletion of CXCR4 in murine hematopoietic progenitors abrogated leukemogenesis induced by constitutively active Notch1, whereas lack of CCR6 and CCR7, which have been shown to be involved in T cell and leukemia extravasation into the central nervous system, respectively, did not influence T cell acute lymphoblastic leukemia development.
High EVI1 expression was detected mainly in myelomonocytic-lineage (designated as e-M4/M5 subtype) leukemia with MLL rearrangements and in megakaryocytic-lineage (designated as e-M7 subtype) leukemia, and its prognostic association was observed in the e-M4/M5 subtype but not in the e-M7 subtype.
These results establish the mechanistic basis underlying the pathogenesis of a severe form of leukemia through aberrant expression of the EVI1 proto-oncogene.
Here, we review the current understanding of the role of Evi1 in controlling the development of leukemia and highlight potential modalities for targeting factors involved in Evi1-regulated signaling.
Overexpression of EVI-1 also occurs with high frequency in leukemia patients without 3q26 abnormalities, and importantly, high EVI-1 expression is an independent negative prognostic indicator irrespective of the presence of 3q26 rearrangements.
These results suggest that EVI1 overexpression was the major factor contributing to leukemogenesis, and the late appearance of the Ph chromosome is closely associated with the progression to an aggressive form of leukemia.
Experimental overexpression of EVI1 by itself was insufficient to cause leukemia in animal model systems, but it cooperated with other genes in this process.
The EVI1 transcriptional repressor is critical to the normal development of a variety of tissues and participates in the progression of acute myeloid leukaemias.
Our results underscore the feasibility of FISH as an adjunct to PCR for the identification of EVI1 deranged leukemias and identified EVI1 as the principal transcript expressed in these malignancies.
Integrations are located in intron 1 or 2, where they promote expression of truncated proteins lacking the PRDI-BF1-RIZ1 homologous (PR) domain, similar to what is observed in human leukemias with EVI1 or PRDM16 mutations.