RUNX1 GENE ROLE IN CANCER
RUNX genes code for transcription factors that are involved in various cellular processes
such as proliferation, differentiation, cell lineage, apoptosis, etc. There are three RUNX
genes.
These RUNX genes acts as both pro-tumorigenic (oncogene) and anti-tumorigenic
(suppressor gene).
GENES
Function associated with
Cancers due to this gene
RUNX1
Hematopoiesis
leukemia, breast, lung and
intestine cancers
RUNX2
Osteogenesis
osteosarcoma, thyroid
carcinoma, breast and
prostate cancer
RUNX3
Formation of gastric
epithelium
Gastric cancer
Runx1 gene is the largest RUNX gene with 260 kb length present on the q arm of 21 st
chromosome in humans. This gene consists of 2 promoter regions due to which it has about
12 isoforms.
The protein coded by this gene is called as RUNX1/AML1 protein. This protein acts a
transcription factor which plays major role in hematopoiesis. This protein is about 50 kDa
with 453 amino acids. RUNX1 protein has 9 exons with two main domains- TAD (Trans
activating domain) and RD (Runt domain). RD (Runt domain) is necessary for DNA binding
and TAD is required for protein-protein interactions. RUNX1 is required for the homeostasis
of hematopoietic stem and progenitor cells, and expansion of hematopoietic stem and
progenitor cells. So the mutations in RUNX1 protein may cause various leukemia. RUNX1 is a
heterodimeric protein which binds with CBFβ and forms a complex which regulates entry
and exit of cell cycle, apoptosis, growth, survival and differentiation pathways.
Various kinds of mutations such as point mutations, non-sense mutations and
chromosomal translocations are responsible for various cancers where chromosomal
translocations are major mutations responsible for leukemia.
Acute myeloid leukemia- Acute myeloid leukemia is most common type and is caused due
to various translocations. Of these t (8; 21) (q22; q22) is the major translocation responsible
for this. This translocation results in the formation of a chimeric protein RUNX1-ETO
(CBFA2T1 protein). This chimeric protein consists of RD domain of RUNX1 and NHR1, NHR2,
NHR3, NHR4 of ETO protein. The RD domain helps in binding with target genes of RUNX1
but because of lack of TAD domain instead of transcriptional activator it acts as
transcriptional repressor. This protein also downregulates the DNA repair enzyme OGG1
which leads to additional abnormalities required for development of AML. This chimeric
protein represses CEBPα which is necessary for differentiation of myeloid progenitors and
activates AP-1 subunit which promotes leukemic self-renewal and expansion.