Mechanisms of Survival and Apoptosis of Leukaemia Cells - Literature review Example

?Mechanisms of Survival and Apoptosis of Leukaemia Cells Leukaemia is a form of blood cancer which is characterised by intense growth of white blood cells. In human body, the cell growth, separation and elimination among others aspects are controlled through apoptosis procedure. It is a mechanism which also controls the evolution and the survival of leukaemia cells. In case of leukaemia, it can be observed that these cells can effectively evade the apoptosis procedure which in turn helps abnormal survival and growth of leukaemia cells in human body. There are various mechanisms which help in the survival of leukaemia cells such as cell signalling, overexpression of anti-apoptotic proteins and inactivation of pro-apoptotic proteins. In leukaemia, severity of defaults in genes such as Galectin-3 genes, BCL2, BCL-X, and BCR among others helps to alter the apoptosis procedure which in turn facilitates the mutation of leukaemia cells. Faults in apoptotic procedure provide self-renewal capability to the leukaemia cells. Table of Contents Literature Review 4 Brief Overview about Leukaemia 4 Apoptosis of Leukaemia Cells 5 Survival of Leukaemia Cells 8 Cell Signalling 8 Overexpression of Anti-apoptotic Proteins 9 Inactivation of Pro-apoptotic Proteins 10 Flt3 Gene for the Survival of Leukaemia Cells 10 Myc Gene for the Survival of Leukaemia Cells 11 Pro-apoptotic and Pro-survival Signalling via B cell receptor (BCR) in Leukaemia 12 BCL2 in Survival of Leukaemia Cells 13 BCL-X in Survival of Leukaemia Cells 14 Galectin-3 for the Survival of Leukaemia Cells 14 References 15 Literature Review Brief Overview about Leukaemia Leukaemia is a type of blood cancer which can either grow rapidly i.e. over days or weeks or grow gradually and constantly i.e. over months and years. A typical blood cell of human beings includes red blood cells, white blood cells and platelets. Blood cells are developed in bone marrow, a soft material residing in the core of bone. Bone marrow comprises hematopoietic cells which are liable for generating red cells, white blood cells and platelets. Leukaemia occurs when underdeveloped white blood cells in the bone marrow split and grow in an intense manner. These underdeveloped blood cells are also known as stem cells. In order to generate a mature blood cell, stem cells must progress through several phases. Thus, it appears that in case of leukaemia, the number of stem cells increases exceedingly. There are two types of stem cells in human body such as Myeloid and Lymphoid which help to generate leukaemia cells (Bupa, 2013). Leukaemia is believed to be an initiation of abnormal growth of white blood cells. In this disease, certain important genes, which regulate the division, multiplication and elimination of blood cells are damaged or transformed. As a result, the blood cells become abnormal. In human body, if the abnormal blood cells survive, they can multiply themselves, gradually become out of control and turn into a deadly disease such as blood cancer. In case of leukaemia, undeveloped white blood cells become abnormal, resulting in intense growth. This growth can crowd the bone marrow and create an impact on the production of other mature blood cells (State Government of Victoria, 2013). There are four major types of leukaemia that have been demonstrated in following figure: The term acute denotes a disease which grows rapidly and chronic means a disease which grows gradually. On the other hand, myeloid signifies abnormal blood cells which are made from myeloid stem cells and lymphoblastic denotes abnormal blood cells which are made from lymphoid stem cells (Kenny, 2012). Apoptosis of Leukaemia Cells Apoptosis or in other words ‘programmed cell death’ is a key factor for a disease such as leukaemia. In accordance with the study of Kerr & et. al. (1972), apoptosis was primarily defined by its morphological nature such as cell contraction, chromatic compression and nuclear disintegration. However, researchers have comprehended that apoptosis has reflective effects for understanding of evolving biology. The study of Lowe1 & Lin (1999) implies that apoptosis can influence the survival of cells and it can control production and spread of cells in human body. According to Dash (n.d.) apoptosis occurs throughout the usual growth of organisms and endures during the human life. The blend of apoptosis and cell production is liable for influencing the cells and organs. Apoptosis is a vital portion of human immune system and diseases such as cancer is often characterised by low level of apoptosis. Under normal situation, damaged cells which cannot be repaired, go through apoptosis and are removed accordingly. However, in case of cancer, the damaged cells escape from going through apoptosis. As a result, the disease progresses to a vulnerable level (Dash, n.d.). The following figure will show the cell death process in apoptosis: Source: (COPE, n.d.) Apoptosis procedure is controlled by several cell signals which can originate through external inducers or internal inducers. According to Gewies (2003), apoptotic process is involved in development, separation, production, regulation and elimination of imperfect & harmful cells. Thus, defects in the apoptosis process can result in spreading of harmful cells which eventually lead to vulnerable diseases such as cancer and acquired immune deficiency syndrome (AIDS) among others. Several cells which are associated with cancer such as leukaemia cells use certain actions in order to stop apoptosis of cells from being eliminated. Kettleworth (2007) stated that defects in internal inducers allow leukaemia cells to obtain extra mutation, survive improperly and to ultimately become malicious. Furthermore, the internal defect in apoptosis also represents the resistance of leukaemia cell to death. It is worth mentioning that internal defect in apoptotic system leads to hyperactive cell production, which supports the creation of leukaemia cell. A decontrolled apoptosis system helps to make genetic alterations in hematopoietic cells, which can block apoptosis process and allow cells to make additional transformations and ultimately become malevolent. Several researches on leukaemia have demonstrated that leukaemia cells invariably have abnormalities in one or in excess of one apoptotic ways. These apoptotic ways control the survival of abnormal blood cells over the normal counterparts. According to Testa & Riccioni (2007), irregularities in apoptotic reaction play an important part in the growth of leukemic cells. There are several biological flaws which are existent in leukemic cells which contribute to their survival and are also related to low rate of reaction to standard treatments. Lapidot (1994) stated that leukaemia is a multistep procedure which is based on progressive genetic changes. These genetic changes determine the conversion of blood cells into leukemic cells. Apoptosis encourages leukemic cells to accumulate, thus instigating further genetic changes. Survival of Leukaemia Cells Cell survival necessitates active inhibition of apoptosis, which is achieved by hindering the pro-apoptotic aspects as well as encouraging anti-apoptotic aspects. It is conjectured that leukaemia cells have to go through constitutive activation of signal pathways in order to survive in human body (Igney & Krammer, 2002). Cell Signalling Dinasarapu & et. al. (2011) stated that cell signalling is a procedure of interaction between cells which controls the simple cellular functions and also synchronises the activities of cells. Any kind of faults in the cell signalling process results in diseases such as cancer. The entire process of cell transformation is induced by receptor activation which is termed as signal transduction or pathway. Receptor protein helps to control the activities of cell such as cell division, destruction and multiplication among others. The pathway includes interaction between different proteins which reside in every cell. The growth aspects of cells are dependent on receptors which encourage cells to progress. According to Lodish & et. al. (2000), signal transduction happens when cellular signalling activates receptor in order to create a reaction in cell. According to Xu & et. al. (2003), in case of AML, PI3K pathway plays a vital part in the survival of leukaemia cell. Activation of PI3K pathway can generate undeveloped leukemic cells. PI3K pathway can activate AKT protein, which impacts the numerous cellular creation procedures such as cell production, cell copy and cell movement. In leukaemia, PI3K pathway minimises apoptosis and allows massive cell production. Most cancer cells are independent of survival signals which protect them from death. This survival of cell is achieved through alterations in AKT pathway. Alterations in AKT pathway facilitates survival signals which results in enhanced inattentiveness of cancer cells to apoptosis initiation (Igney & Krammer, 2002). The following figure will show the AKT pathway: Source: (Life Technologies Corporation, 2013) Overexpression of Anti-apoptotic Proteins Cell can acquire the ability of resistance of apoptosis through several mechanisms and one of the popular mechanisms is overexpression of anti-apoptotic protein. A common feature of leukaemia is enhanced expression of anti-apoptotic protein. Several studies have demonstrated the relationship between high level of expression of anti-apoptotic protein and severity of leukaemia. Overexpression results in the resistance of leukaemia cells towards several types of therapeutic drugs and medical treatments. In this way, overexpression of anti-apoptotic proteins contributes to the formation of leukaemia cells and helps them to survive in human body (Igney & Krammer, 2002). Inactivation of Pro-apoptotic Proteins Apart from overexpression of anti-apoptotic proteins, leukaemia cells can also obtain apoptosis resistance ability by inactivation of pro-apoptotic proteins. In certain types of cancer, pro-apoptotic genes are mutated through inactivation of pro-apoptotic proteins. Inactivation of anti-apoptotic proteins is related with weak reaction rate of therapy (Igney & Krammer, 2002). Flt3 Gene for the Survival of Leukaemia Cells Flt3 gene is considered as a cytokine receptor protein which has caught enough attention amid researchers for understanding its role in the survival of leukaemia cells. Cytokine receptor is directly associated with the deliberation of immune deficiency condition in human body. It is believed that Flt3 signalling is important for the generation of stem cells in human body. Flt3 gene is a mutated gene which is associated in the survival of AML cells. According to the study of Yamamoto & et. al., (2001), Flt3 gene has been found in several AML affected patients. Xu & et. al., (2003) stated that AML results from genetic alterations, which leads to the overexpression of transcript fusion proteins. Transcript fusion proteins collaborate with the evolution or survival signalling in order to produce a completely transformed leukaemia cell. Furthermore, researchers also demonstrate that a considerable proportion of AML circumstances are related with mutation of Flt3 gene which acts as evolution stimulatory protein for AML. Myc Gene for the Survival of Leukaemia Cells Myc is a regulator gene that can control the expression of one or in excess of one gene. The mutated version of Myc can be found in the creation of cancer related cells. Mutated Myc can result in free expression of several genes, and some of these genes are involved in cell production, resulting in the formation of leukaemia. According to the study of Lynch & et. al. (2013), tetratricopeptide repeat domain (TTC5) and EP300 can result in strong growth of Myc protein which can contribute to the stimulation of apoptosis. It can change the balance between overexpression of anti-apoptotic proteins and pro-apoptotic proteins, therefore supporting the resistance of cell towards apoptosis. On the basis of the study of Lynch & et. al. (2013), it has been identified that TTC5 is required for the survival of AML cells. TTC5 plays a vital part in Deoxyribonucleic acid (DNA) destruction in human body. TTC5 can enhance the function of EP300, a protein which controls the activity of cells in the body. EP300 determines the cell development and cell division process, hence stimulating cells to mature. TTC5 enhances the activity of EP300 which results in greater acetylation, constancy and transcriptional instigation throughout DNA damage response. TTC5 maintains the manifestation of BCL2 in AML cells, either directly or indirectly. As a result, it helps in the survival of leukaemia cells. Pro-apoptotic and Pro-survival Signalling via B cell receptor (BCR) in Leukaemia B cell receptor (BCR) is considered as a receptor protein situated in B-cells. B-cells are a type of white blood cells which play a vital role in the human immune system. BCR comprises antibody and thus defects in BCR can result in the inefficiency of immune system, making human beings vulnerable to any kind of disease. The management of leukaemia cells has significantly progressed in the last few decades with the initiation of targeted therapy. According to Scupoli & Pizzolo (2012), the growth of leukaemia includes BCR which governs the survival of leukaemia cells. BCR signalling overwhelms the apoptosis and hence contributes to the growth of leukemic cells. Several experiments demonstrate that BCR stimulation is capable of transmitting survival signals to the cells which are related with the enhanced activation of leukaemia cells. According to Zhang & Li (2013), several molecular signalling pathways are liable for the development of stem cells and thus act as a survival mechanism for leukaemia cells. One of the important pathways influencing the survival of leukaemia cells is BCL pathways. Several studies specify that BCL plays a vital part in the feedback signalling system of leukaemia cells in reaction to any kind of diagnosis treatment. The cancer cells are characterised by its self-renewal ability which also serves as a survival factor for leukemic cells. Leukemic cell has the capability to self-renew and it transmits the disease into secondary recipients. It is widely acknowledged that leukaemia cells are addicted to BCR kinase function, and BCR activates several downstream signalling pathways which are critical in encouraging leukemic cells through regulating cell propagation and survival. The study of Stevenson & et. al. (2011) depicted that BCR is one of the key survival particles for normal cells in human body. The studies on leukaemia have revealed the fact that the subsets of leukaemia cells have developed from distinct BCR. According to Messmer & et. al. (2005), normal BCR reacts to the antigen by explosion and differentiation. In Chronic Lymphocytic Leukaemia (CLL), it can be observed that B-cells apparently react to the antigen, which presumably leads to the proliferation and survival. BCL2 in Survival of Leukaemia Cells BCL2 is considered as a component of regulator proteins which can control apoptosis. The damage of BCL2 is recognised as the key reason for leukaemia. BCL2 is an anti-apoptotic gene which hinders the apoptotic process. If anti-apoptotic genes are overexpressed, it can result in the survival of cells which is a vital characteristic of any type of cancer. However, it is worth mentioning that overexpression of BCL2 alone cannot cause a cancer such as leukaemia. Still constant overexpression of BCL2 can generate cells in an aggressive manner. Leukaemia occurs as the outcome of disruption in the balance between cell growth and cell destruction. There are also evidences that defective apoptosis can result from abnormal expression of BCL2 in human body, resulting in leukaemia cell growth (Glantz & et. al., 2005). BCL-X in Survival of Leukaemia Cells In addition to BCL2, there is other anti-apoptotic protein which is involved in the resistance of apoptosis namely BCL-X. BCL-X can confer resistance to numerous apoptosis processes comprising pathways in cell positions as well as appears to be unfettered by constitutively active mutant cells (Igney & Krammer, 2002). Galectin-3 for the Survival of Leukaemia Cells According to Cheng & et. al. (2011), Galectin-3, a lectin protein is highly associated with the survival of leukaemia cell from apoptotic process. Galectin-3 facilitates the survival of cells through the resistance in apoptosis. From the researches, it has been observed that this protein can alleviate the BCL2 protein which is vital for the escape of leukaemia cells from apoptotic inducements. According to the study of Yamamoto-Sugitani & et. al. (2011), galectin-3 which is invigorated by leukaemia cell can ratify drug resistance. Moreover, the study also depicted that gelectin-3 expression supports molecular signalling pathway for disease maintenance and results in the survival of leukaemia cells. References Bupa, 2013. Leukaemia - An Overview. Health Information. [Online] Available at: http://www.bupa.co.uk/individuals/health-information/directory/l/leukaemia-and-lymphoma [Accessed June 17, 2013]. Cheng, Y. L. & et. al., 2011. Increased Galectin-3 Facilitates Leukaemia Cell Survival From Apoptotic Stimuli. Biochemical and Biophysical Research Communications, Vol. 412, No. 2, pp. 334-340. COPE, No Date. Apoptosis. Apoptin-Associating Protein-1. [Online] Available at: http://www.copewithcytokines.de/cope.cgi?key=Apoptosis [Accessed June 17, 2013]. Dash, P., No Date. Apoptosis. St. George’s University of London. 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Galectin-3 (Gal-3) Induced By Leukaemia Microenvironment Promotes Drug Resistance and Bone Marrow Lodgment in Chronic Myelogenous Leukaemia. Proceedings of the National Academy of Sciences, Vol. 108, No. 42. Zhang, H. & Li, S., 2013. Molecular Mechanisms for Survival Regulation of Chronic Myeloid Leukaemia Stem Cells. Protein & Cell, Vol. 4, No. 3, pp. 186-196. Read More