Although it is unlikely that the Rb gene is directly involved in this translocation, the loss of the Rb gene product combined with the activation of the EVI1 gene may have led to the development of leukemia.
There is no evidence of ongoing in vivo clonal expansion of the Mds1/Evi1 populations, and all animals are hematologically normal without evidence for leukemia.
In this paper, we have analyzed chromosomal rearrangements in two leukemia cell lines derived from CML-BC with inv(3)(q21q26) and have identified the breakpoints within the EVI1 coding area.
The human PRDI-BF1 or BLIMP1 gene and its mouse homolog Blimp1 are members of the recently realized PR domain family that includes the retinoblastoma interacting zinc finger gene RIZ and the MDS1-EVI1leukemia cancer gene.
EVI-1 (ecotropic virus integration site-1) was at first identified as an integration site of the murine leukemia retrovirus in murine myeloid leukemias.
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).
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.
We propose that rearrangements at 3q26 involving EVI1 could result in leukemia by a two-step process involving first transcriptional disruption of MDS1/EVI1, and next by inappropriately activating expression of EVI1.
Specific gene activation (N-myc, evi-1) or fusion genes such as the alpha retinoic acid receptor (alpha RAR) and pml have been identified as the specific cause of some cases of leukemia.
Characterization of the RUNX1-PRDM16 fusion protein and comparison with the RUNX1-MDS1/EVI1 protein will facilitate the understanding of the mechanisms underlying RUNX1-associated leukemia.
These studies clearly indicate an essential role of PR-domain protein ME in MFP leukemia, suggesting that ME may be a novel target for therapeutic intervention for this group of leukemias.
MDS1/EVI1 enhances TGF-beta1 signaling and strengthens its growth-inhibitory effect but the leukemia-associated fusion protein AML1/MDS1/EVI1, product of the t(3;21), abrogates growth-inhibition in response to TGF-beta1.