Acute Myeloid leukemia (AML) is a cancer of the blood stem cells with a drastic increase and arrest in myeloid progenitors.[1, 2] Due to rapid growth of abnormal cells, granulocytes, platelets, red blood cells are reduced in number, with or without leukocytosis. [2]It is one of the deadliest types of cancer, with an incidence rate of 12.6 people per 100,000 over 65 in recent years.[5] Stem cell transplants, radiotherapy and chemotherapy are usually used in the treatment of acute myeloid leukemia. [3, 5]AML can be caused by several factors including intrinsic (translocation) and extrinsic factors (microenvironment).[4, 5] The effect of growth factors as extrinsic factors on leukemic cell proliferation is noteworthy. [4]Growth factors influence both normal and leukemic cells by influencing transcription and translation.[10, 19] In addition to bone marrow, growth factors can be derived from other tissues as well. Several studies have shown that growth factors from other tissues can have a profound effect on the proliferation of hematopoietic cells.[3, 6] Growth factors like hormones are usually secreted from exocrine glands. [3, 10]The anterior pituitary gland secretes growth hormone that is responsible for driving the growth and proliferation of a variety of cells, depending on whether it affects the cells by means of intermediates or on its own.[8, 20] Insulin-like growth factor (IGF) is a mitogenic intermediate produced by the liver that is responsible for regulating growth and proliferation in response to growth hormone (GH).[7, 19] There are two proteins in this family, IGF1 and IGF2, which interact with the cell surface through their receptors, causing the proliferation of cells when these proteins interact with the surface of the cell.[3, 19] IGFBP3 also has an important role in the regulation of IGF1 and IGF2, as it binds to their receptors in order to prevent them from interacting with each other.[15, 18]
The IGF1R is the receptor tyrosine kinase that binds both IGF1 and IGF2.[6, 15] As a result of this receptor, it activates the AKT pathway (vital for cell proliferation) as well as the Ras-MAPK pathway which plays a significant role in ELK1 transcription.[15] The IGF2R, however, binds specifically to IGF2, and it does not possess either tyrosine kinase activity or mitogenic activity.[11, 17]
Among the many proteins that play a role in proliferation, IGF1 is one of the most notable.[3, 18, 19] In the present study, it was demonstrated that the expression levels of the IGF1 gene were significantly higher in AML patients as compared to normal subjects, which is in accordance with our hypothesis. The expression levels of this gene, however, did not show any statistically significant correlation with the demographic characteristics of the population. Mayer and colleagues published a study in 2016 examining the expression levels of IGF1 and IGFBP3 genes in patients with CLL. In this study, IGF1 gene expression levels were elevated than expected. As well, this similarity in AML patients can be attributed to the fact that the IGF family can play a significant role in the growth of malignant cells in this disease. [21]
The results obtained in the present study are similar to those which were obtained in an earlier study conducted in 2019 by Jia-Min Zhang and colleagues. It was determined that in their study, by examining the expression levels of both IGF1, which are a main member of the IGF family, the level of IGF1 gene expression increased in patients who had AML. [22]
It was found that IGF1R expression levels were higher in AML patients, possibly due to the excessive effect of IGF1 on its receptor, which causes cell division. Although it had a higher expression level in the IGF1R gene, there was no meaningful correlation with demographic data.
IGF2, the second member of this family, is the ligand for IGF2R. It was found that the expression levels of IGF2 gene were lower in AML patients compared with the control group, while there was no significant correlation between expression levels and demographic information. According to the ROC curve, there was no significant increase in IGF2 gene expression in patients when compared to the control group. The difference in expression of IGF2 between normal controls and AML patients was not statistically significant when it is considered that IGF2 has a small impact on cell proliferation. As a result, the present study and previous studies have concluded that IGF2 plays a less significant role in the signaling pathways of cell proliferation in comparison with other IGF family.
In the study conducted by Pollak et al. in 2004, IGFBP3 was reported to have a reduction in AML patients, in comparison with the control group but the present study’s findings are incompatible with the aforementioned data.[19] In 2015, Karmali and et al. reported an increase in IGFBP3, IGFBP2, IGFBP1 and IGFBP6 in patients with AML.[23] According to the study, IGFBP3 expression levels have also increased, which is in accordance with the two studies conducted in 2015, but incompatible with the study conducted in 2004.