MECOM has been described as a proto-oncogene since its first discovery in 1988. Overexpression and aberrant expression of MECOM has been associated with human
acute myelogenous leukemia (AML),
myelodysplastic syndrome (MDS) and
chronic myelogenous leukemia (CML), and more recently has been shown to be an indicator of poor prognosis. Its function in these cells may be regulated by phosphorylation of serine196, in its
N-terminal DNA binding domain. All of these involve erratic cellular development and differentiation in the bone marrow leading to dramatic alterations in the normal population of blood cells. MECOM has also been found to play a role in solid ovarian and colon tumors, although it is not yet well characterized in this context. It has been hypothesized that it acts as a survival factor in tumor cell lines, preventing therapeutic-induced
apoptosis and rendering the tumor cells more resistant to current treatments.
Role in tumor suppressor signaling and prevention of apoptosis TGF-β and cell cycle progression MECOM has been shown to be involved in the downstream signaling pathway of
transforming growth factor beta (TGF-β). TGF-β, along with other TGF-β family ligands such as
bone morphogenic protein (BMP) and
activin are involved in regulating important cellular functions such as proliferation, differentiation, apoptosis, and matrix production. These biological roles are not only important for cellular development, but also in understanding oncogenesis. TGF-β signaling induces transcription of the
cyclin-dependent kinase (CDK) inhibitors p15Ink4B or p21Cip1, which, as a consequence, act to halt the cell cycle and stop proliferation. This inhibition can lead to cellular differentiation or apoptosis, and therefore any resistance to TGF-β is thought to contribute in some way to human leukemogenesis. The downstream effectors of TGF-β are the
SMAD proteins.
SMAD2 and
SMAD3 are phosphorylated in response to TGF-β ligand binding at a
TGF-β receptor, and translocate into the nucleus of the cell, where they can then bind to DNA and other transcription factors.
JNK and inhibition of apoptosis c-Jun N-terminal kinase (JNK) is a MAP kinase activated by extracellular stress signals such as gamma-radiation, ultraviolet light, Fas ligand, tumor necrosis factor α (TNF-α), and interleukin-1. Phosphorylation on two separate residues, Thr183 and Tyr185, cause JNK to become activated and translocate to the nucleus to phosphorylate and activate key transcription factors for the apoptotic response. It has subsequently been shown many times
in vitro that MECOM upregulation can induce proliferation and differentiation of HSCs and some other cell types such as rat fibroblasts. Upregulation of Tie2 has been shown to occur under hypoxic conditions, and to increase angiogenesis when coinjected with tumor cells in mice. The complete physiological repercussions of this complex role of MECOM have yet to be elucidated, however, could provide insight into the wide variety of results that have been reported regarding the effect of MECOM on
in vitro cell proliferation. This can lead to aberrant expression of MECOM, and,
as shown in the figure below, commonly involved chromosomal breakpoints have been mapped extensively. One major cause of MECOM activation and consequent overexpression is a clinical condition called
3q21q26 syndrome from inv(3)(q21q26) or t(3;3)(q21;q26). next to the MECOM coding sequence, resulting in a dramatic increase of MECOM levels in the cell. The most common circumstance involves chromosomal translocations in human
AML or
MDS, leading to constitutive expression of MECOM and eventually to cancer. In addition, it has been shown that development of
acute myelogenous leukemia is likely due to several sequential genetic changes, and that expression of MECOM or its chimeric counterparts ME and AME alone is not enough to completely block myeloid differentiation.
BCR-Abl, a fusion gene caused by t(9;22)(q34;q11)is thought to have a cooperative effect with MECOM during the progression of AML and CML.
Pharmacogenomics and cancer treatment Very little research has been done in an attempt to therapeutically target MECOM or any of its chimeric counterparts. However, since it has become an established fact that overexpression of MECOM derivatives is a bad prognostic indicator, it is likely that the literature will begin to examine specific targeting within the next few years. One very promising therapeutic agent for myelogenous leukemia and potentially other forms of cancer is
arsenic trioxide (ATO). One study has been done showing that ATO treatment leads to specific degradation of the AML1/MDS1/MECOM oncoprotein and induces both apoptosis and differentiation. As of 2006, Phase I and II clinical trials were being conducted to test this compound on a wide variety of cancer types, and currently (2008) a number of publications are showing positive outcomes in individual case studies, both pediatric and adult.
Hormones The important and essential role of MECOM in embryogenesis clearly indicates a close association with hormonal fluctuations in developing cells. However, to date, the presence of MECOM in cancer has not been linked to aberrant production of any hormones or hormone receptors. It is likely that MECOM is far enough downstream of hormonal signaling that once overproduced, it can function independently. ==Future and current research==