Molecular Mechanisms of Acute Myeloid Leukemia and AML Treatments
Cancers such as leukemia and lymphoma are hematologic diseases that affect millions of Americans each year. Specifically, acute myeloid leukemia, which is also known as AML, is considered to be one of the most frequently occurring types of leukemia and is a major cause of mortality in the United States. Acute myeloid leukemia is infamous for being challenging to treat, due to the capability of the cells forming resistance to treatment. Therefore, it is critical to understand the molecular mechanisms of the hematologic disease and the molecular mechanisms of the treatments used against the disease to better understand how the resistance forms and to better treat the disease.
Acute myeloid leukemia has several critical molecular mechanisms that are responsible for the malignant alteration of the cells involved in the disease (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.344). Normal cells in the body go through apoptosis. Apoptosis is the planned and programmed death of a cell (Orlova, Lebedev, Spirin, & Prassolov, 2016, p. 344). Two pathways signal for the cell to undergo apoptosis, one pathway is known as an intrinsic pathway and the other an extrinsic pathway. The apoptosis mechanisms are characterized by ligand-binding, and the mechanism is mediated by a cascade known as the caspase cascade (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.344). In humans, twelve caspase cascades have been identified and the twelve cascades can be grouped as either initiator enzymes or effector enzymes (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.344). Caspase cascades are composed of cysteine proteases. Cysteine proteases are responsible for the cleavage of polypeptide chains after aspartate residues (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.344). Overall, caspases are involved in several crucial functions in the cell such as apoptosis, inflammation, and the maturation of lymphocytes (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.344). Caspases clearly have numerous important functions. Another function of caspases is to inactivate the proteins that are involved in blocking apoptosis (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.345). An example of caspases involved in blocking apoptosis are the proteins in the family known as the Bcl-2 family. The Bcl-2 family is a family of proteins located in the mitochondrial membrane, and the proteins alter the permeability of the membrane (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.345). This particular family of proteins are broken down by the caspases (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.345).
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In association of the caspase cascade pathways that are involved in the malignant alteration of the cells, another aspect involved in the cells of AML are the signaling pathways of apoptosis. In patients with acute myeloid leukemia, it is generally thought that dysfunction in the process of apoptosis causes the disease to progress (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.345). The signaling pathways of apoptosis are responsible for regulating the amount of signals that are sent out and the amount of inhibitors that are produced for controlling apoptosis. Patients with AML have been found to have an increased amount of the Bcl-2 protein due to the signaling pathways. Increased Bcl-2 causes the cells to continue transforming normal cells into malignant cells because the Bcl-2 blocks apoptosis (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.345). In general, it is typical for cells in patients with leukemia to show apoptosis deficiencies (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.345). Something to further consider is that it has been observed that by prohibiting the Bcl-2, patients potentially have a more positive survival rate (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.345).
A third molecular mechanism pathway that, in conjunction with the two previously mentioned mechanism, contributes to the formation of the malignant cells in AML is the Hedgehog signaling pathway. Cancer develops due to disorders related to uncontrollable cell proliferation and differentiation (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.347). The Hedgehog signaling pathway is a cascade that sends critical information to embryonic stem cells regarding correct cell differentiation (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.347). The Hedgehog signaling pathway is comprised of hedgehog genes, and these are responsible for regulating correct embryonic development through different processes. The gene family known as Hh genes are very important for embryonic development and have been recently greatly studied due to their importance. The Hh family genes include the following genes: Desert Hh, Indian Hh, Shh, Ptc 1, Ptc2, Gli 1, Gli2, and Gli3 (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.347). Each of these specific genes are involved in a select multitude of processes such as: embryo human development, regulating spermatogenesis, and coordinating cell proliferation (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.347) Additionally, the Hedgehog signaling pathway has three main components. The components of the signaling pathway include the Hh ligand, a G protein-coupled receptor, and a cytoplasmic complex. Ci and Gli are transcription effectors that are regulated by the cytoplasmic complex (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.347). The G protein-coupled receptor contains the Ptc negative regulator as well as the activator of Smo (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.347).
The molecular mechanism that causes the cancerous acute myeloid leukemia cells to be created continues with the binding of the ligand of the Hedgehog signaling pathway to Ptc. Ptc-Smo is an interaction that alters the pathway and makes it so that Smo is no longer inhibited (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.347). When Smo is no longer inhibited, Gli is able to activate transcription by entering into the nucleus (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.347). Cell differentiation lineages are developed due to Gli entering the nucleus because of the alteration that results from Smo not being inhibited. Therefore, when the Hedgehog signaling pathway is disrupted, it can affect cell proliferation and cause cells to develop resistance. Immense studies have been starting to occur, because of the fact that if Hh genes can be regulated, then this could be a method used for treatment in patients with AML (Orlova, Lebedev, Spirin, & Prassolov, 2016, p.347).
Treatments for acute myeloid leukemia range from chemotherapy to radiation, and combination of other treatments. However, it is important to also understand the molecular mechanisms for the cancer treatments to try and understand any resistance that may occur to the treatment and to try and prevent it. Presently, the most optimal treatment for acute myeloid leukemia is considered to be total body irradiation coupled with chemotherapy (Meng et al., 2015). This means that it is important to analyze the molecular mechanism of the Hedgehog signaling pathway, because that particular pathway is utilized in acute myeloid leukemia treatment and cells often development a resistance to the treatment. There are two molecular mechanisms for treatments that are going to be the main focus, these two mechanism are: the Hedgehog signaling pathway, and the targeting of CD44.
As previously mentioned, the Hedgehog pathway is a stem cell pathway and therefore it is a good target for treatment in patients with AML. The Hedgehog pathway also has been known to acquire resistance to chemotherapy along with being efficient at renewing cells (Aberger, Hutterer, Sternberg, Burgo, & Hartmann, 2017, p. 3). Recently, targeting the Hedgehog pathway with inhibitors has been a high research study interest. The Hedgehog pathway is responsible for regulating stem cells in leukemia, as well as being responsible for eventually acquiring resistance to the drug-therapies in AML patients. Consequently, to treat AML patients by targeting the Hedgehog pathway, the first step is to modify the human myeloid cell lines (Aberger, Hutterer, Sternberg, Burgo, & Hartmann, 2017, p.3). The human myeloid cell lines are called HL60. Human myeloid cell lines include HL60/RX, which displays drug resistance, and HL60/ADR, which shows elevated levels of GLI1 and SMO, according to the researcher Li and his colleagues (Aberger, Hutterer, Sternberg, Burgo, & Hartmann, 2017, p. 3). Treatment for AML can be achieved by causing the inhibition of the Hedgehog pathway using LDE225, which is the antagonist of SMO (Aberger, Hutterer, Sternberg, Burgo, & Hartmann, 2017, p. 4). The inhibition of the Hedgehog pathway using LDE225 requires the down-regulation of the pathway called GLI1/PI3K/AKT/NF-kB (Aberger, Hutterer, Sternberg, Burgo, & Hartmann, 2017, p. 4). Using LDE225 to inhibit the Hedgehog pathway results in the cells being unable to repair their DNA after radiation, and increased levels of apoptosis of the cells (Aberger, Hutterer, Sternberg, Burgo, & Hartmann, 2017, p. 4). Ultimately, pairing inhibition of the Hedgehog signaling pathway with chemotherapy results in better outcomes for acute myeloid leukemia patients.
A second option for targeting the Hedgehog signaling pathway for AML treatment involves the Human Hedgehog-interacting protein. The Human Hedgehog-interacting protein is a glycoprotein, and the way it functions is to bind to the Hedgehog signaling pathway and inhibiting its ligand function (Aberger, Hutterer, Sternberg, Burgo, & Hartmann, 2017, p. 5). Human Hedgehog-interacting protein has been proven to subdue the production of leukemic cells that cause acute myeloid leukemia. On the contrary, if the Human Hedgehog-interacting protein is suppressed and its expression is reduced it actually contributes to the severity of the acute myeloid leukemia (Aberger, Hutterer, Sternberg, Burgo, & Hartmann, 2017, p. 5).
A third target for treating acute myeloid leukemia in relation to the Hedgehog signaling pathway is to target GLI1. High levels of GLI1 being expressed has been known to correspond with high levels of DNA methyltransferase 1 being expressed (Aberger, Hutterer, Sternberg, Burgo, & Hartmann, 2017, p. 6). DNA methyltransferase 1 is also known as DNMT1 causes malignant cell proliferation and a lower survival rate (Aberger, Hutterer, Sternberg, Burgo, & Hartmann, 2017, p. 6). Thus, using an antagonist as GLI to inhibit the binding of DNA methyltransferase 1 and GLI1 will increase the survival rate and decrease the malignant cell proliferation (Aberger, Hutterer, Sternberg, Burgo, & Hartmann, 2017, p. 6). Ultimately, by combining the use of the antagonists again GLI with drugs that are demethylating, acute myeloid cancer patients can be treated effectively (Aberger, Hutterer, Sternberg, Burgo, & Hartmann, 2017, p. 6).
Acute myeloid leukemia can also be treated by targeting CD44, which destroys acute myeloid leukemia stem cells. Acute myeloid leukemia stem cells are infamous for their ability to renew themselves, and their ability to self-replenish creates substantial amounts of leukemic blasts (Deisseroth, 2005). Presently, chemotherapies target the leukemic stem cells that are proficient at proliferating themselves, however, these treatments easily develop resistance. That is why targeting CD44 has been a new focus area for treatment. CD44 is a transmembrane glycoprotein that can be spliced to create several different isoforms (Deisseroth, 2005, p. 1168). Additionally, CD44 mitigates cell-cell interactions, is responsible for adhesion through ligand binding, and can transmit intracellular signals (Deisseroth, 2005, p. 1168). In patients with acute myeloid leukemia, high levels of CD44 isoforms are present, and the presence of certain isoforms have been documented to lead to poor outcomes for acute myeloid leukemia patients (Deisseroth, 2005, p. 1168). Thus, to target CD44, mAbs first has to be activated. Monoclonal antibodies, which is what mAbs stands for, bind through ligation to the CD44 (Deisseroth, 2005, p. 1169). The binding of the monoclonal antibodies to CD44 inhibits its normal activity, causes proliferation no longer to occur, and activates apoptosis in the cells (Deisseroth, 2005, p.1169).
Overall, understanding the molecular mechanism for acute myeloid leukemia is very clinically relevant. AML affects millions of people in the United States annually, and it is a major cause or mortality. The mechanism for the malignant transformation of normal cells to cancerous cells involves uncontrolled cell proliferation and issues with cellular apoptosis. By means of extensive research, it has been determined that with combined methods, AML can be treated by targeting the Hedgehog signaling complex, along with another mechanism that involves CD44. Acute myeloid leukemia is a hematologic disease that affects numerous people, but with the ability to understand the molecular mechanisms that make up the disease and the disease treatments, proper actions can be taken to target the specific mechanisms to give patients a more promising outcome.