Signalization mediated by Insulin-like Growth Factor in mesenchymal and leukemic cells in Acute Myeloid Leukemia

Abstract

Acute Myeloid Leukemia (AML) is characterized by the proliferation of hematopoietic progenitor cells presenting a block of differentiation, resistance to apoptosis, and deregulation of the cell cycle and senescence. Among the genetic aberrations described in AML, the chromosomal translocations are particularly well characterized. They lead to the formation of fusion genes, which are involved in the molecular mechanism of the disease and are important prognostic markers. Nevertheless, approximately 40% to 50% of AMLs have a normal karyotype. Recent studies have identified mutations in approximately 60% of these. In addition to the genetic abnormalities of the leukemic cells, the role of the bone marrow microenvironment has been postulated but remains controversial. It is known that mesenchymal stem cells (MSCs) have an important role in tumor progression by secreting growth factors that act on receptors that signal pathways of cell proliferation and survival, especially PI3K/Akt and RAF/MEK / ERK. One of the hormone systems that operate in this manner is the IGF system, which has some components known to be secreted by MSCs. There is some evidence of IGF alterations in LMA. Loss of genomic imprinting of IGF2 has been described in patients with the disease and was associated with increased gene expression and secretion of autocrine IGF2. From the clinical point of view, the increase in gene expression and plasma levels of IGFBP-2 has been linked to resistance to conventional chemotherapy of AML patients. Corroborating these findings, Kühnla et al. (2011) reported that increased expression of IGFBP-2 has been linked to poor prognosis in AML. Chapuis et al. (2010) suggested that there may be a continuous activation of the PI3K/Akt pathway by an autocrine regulation by IGF-1 in leukemic cells isolated from the bone marrow of newly diagnosed AML patients. However, it was not soundly demonstrated that the leukemic cells secrete IGF-1. Thus, we believe that, in addition to an autocrine activity of the leukemic cells, there is also an important role played by IGF paracrine secretion by mesenchymal cells present in the bone marrow.(AU)