Musashi-2

MSI2 belongs to the RNA-processing group of proteins which are associated with the transcription factor SOX2 during the early stages of differentiation. SOX2 is known to be essential during embryogenesis and in the self-renewal and pluripotency of embryonic stem cells. MSI2 has a high influence on it too, since the gain or loss of self-renewal capacity and the extent of differentiation depends on MSI2 levels. Although both of the isoforms of this protein are needed to the maintenance of the self-renewal, they are different on a functional way and they play different roles in some aspects of the process. For example, only isoform 1 expression is related to the cloning efficiency of embryonic stem cells.[12]

In a similar way to MSI1, MSI2 is also active in the proliferation of pluripotent neural precursors cells of the embryo, during which both MSI1 and MSI2 are strongly co-expressed. Moreover, MSI1 and MSI2 regulate the multiplication and maintenance of a specific group inside of neural precursors cells: CNS (central neural system) stem cells populations. Therefore, MSI2 plays a significant role in the development and maintenance of CNS stem cells through post-transcriptional gene regulation.[7]

MSI2 is present in blood cells, in which its expression is situated in the hematopoietic system, more commonly in the most primitive cells. These are the LSK cells, which are composed by long-term hematopoietic stem cells (LT-HSCs), short-term HSCs (ST-HCSs) and multipotent progenitors (MPPs).[6]

Self-renewal and differentiation processes in hematopoietic stem cells need to be highly regulated in order to maintain homeostasis and to avoid the growing of blood cell malignancies. It is this point is where Musashi-2 interferes.[9] Therefore, MSI2’s function in HSCs consists of regulating their proliferation and differentiation. Therefore, a decreasing on the level of MSI2 induces a reduction in the number of more primitive progenitors of HSCs.[6]

It has been found that MSI2 plays an important role in myeloid leukemia. In both of chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML), MSI2 regulates hematopoietic stem cell proliferation and does not allow the differentiation of its gene expression.[7]

Chronic myelogenous leukemia (CML) progresses from the initial phase, where differentiated myeloid cells are accumulated, to the accelerated phase, where the expansion of these cells increases, and it ends with the blast crisis phase. It has been found that MSI2 participates together with BCR-ABL gene to stimulate the progress to the aggressive phase.[7] The first evidence to consider its role in this phase is its high concentration compared with the first phase of the disease. One of the functions of the MSI2 is to regulate the expression of NUMB, causing its inhibition.[13] Therefore, the function of the MSI2 in this disease is being studied together with Numb expression. However, while Numb is overexpressed during the chronic phase and decreases in the blast one, Musashi starts to be overexpressed in the last fatal phase of CML.[14] The high expression of MSI2 interrupts the cellular differentiation and allows the expansion of immature leukemic cells causing the progress to the deadly phase.[14]

As acute myeloid leukemia (AML) has a similar behavior to the aggressive phase of the CML, MSI2’s role is similar there as well. It has been found that MSI2 is overexpressed in this type of leukemia and its activity is related with Numb consequently. Moreover, the high expression of MSI2 is related with a poor clinical outcome.[6] In order to prove this, it has been demonstrated that with MSI’s knockdown leads to a rising apoptosis and differentiation and to a decreasing proliferation.[14] As a result, patients that develop leukemia without a high expression of MSI2 have a better prognostic.