Role of Caspase 8 6N Deletion/Insertion in Chronic Myeloid Leukemia

Author Name: S. Vishnupriya, *Ahmed Waleed Majeed, E. M Prajitha
Author Email: am.waleed86@gmail.com

Abstract

Chronic myeloid leukaemia (CML) is a type of cancer that affects the blood and bone marrow. Most people diagnosed with CML have a genetic abnormality in their blood cells called the Philadelphia (Ph) chromosome. The Ph-chromosome causes the production of an enzyme called tyrosine kinase which leads to CML Caspase 8 gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes composed of a prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This protein is involved in the programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD-like death effector domain of this protein suggests that it may interact with Fas-interacting protein FADD This study comprises of 50 CML cases from Nizam’s institute of medical sciences, Hyderabad and 50 age and sex matched controls from the local population. DNA was isolated from blood samples collected from both the groups and genotyping was done by Bi-directional PCR Allele-Specific amplification (bi-PASA) using Sequence Specific Primers

Keywords

chronic myeloid leukemia, apoptosis, caspase8, cancer, polymorphism

Introduction

Leukemia is cancer of the blood or bone marrow (which produces blood cells). A person who has leukemia suffers from an abnormal production of blood cells, generally leukocytes (white blood cells). CHRONIC MYELOGENOUS leukemia (CML) is a clonal myeloproliferative disorder of the primitive hematopoietic stem cell. It involves the myeloid, erythroid, megakaryocytic, and sometimes T-lymphoid elements, but not the marrow fibroblast. CML is characterized by the heterogeneity of the disease among patients, a biphasic or triphasic course and the presence of a chromosomal marker, the Philadelphia chromosome (Ph) in the leukemic Proliferation is a shared feature of CML and other myeloproliferative disorders such as essential thrombocytosis, polycythemia vera and myeloid metaplasia/myelofibrosis. Although these entities are usually distinct, overlap in presentation is occasionally observed resulting in diagnostic confusion. Thus, it is important to confirm the diagnosis of CML by cytogenetic (Ph chromosome) or molecular studies, because the natural history and treatment of the myeloproliferative disorders are different. CML is the rarest of the four main types of leukaemia. It occurs mainly in adults and becomes more common with increasing age. The average age at diagnosis is 50 years. It is very rare in children. It is more common in men than in women. CML is a malignancy that is consistently associated with an acquired genetic abnormality, the Philadelphia chromosome. Ph is present in >90% of patients and is the result of a rearrangement between the BCR and Abelson genes. The BCR-ABL fusion gene, is seen in up to 95% of CML patients and gets translated into an oncoprotein, p210BCR/ABL. Approximately 90% of patients with CML have an acquired genetic abnormality, the Philadelphia chromosome (Ph). The Ph is a shortened chromosome 22 resulting from a reciprocal translocation between the long arms of chromosomes 9 and 22 t (9; 22q34; q11).
Genetic instability due to dysfunction of DNA repair has long been considered a cause of the non-random chromosomal abnormalities that contributes to disease progression. However, not all the studies support the notion of genomic instability in CML. Additionally, whether genomic instability is a cause or effect of disease progression is also not known. The symptoms of CML
include chills, sweating, fever without infection, and fatigue. Later symptoms of chronic myelogenous leukemia are due to decreasing function of the bone marrow. A diagnosis of CML (chronic myeloid leukaemia) is often suspected in patients with persistent unexplained leukocytosis and/or splenomegaly. The work-up for these patients includes a complete blood count, with a cellular differential and platelet count. Apoptosis or programmed cell death can be considered a protective mechanism against cancer and its derangement has significance in many malignancies. In CML, multiple mechanisms contribute toward resistance against apoptosis. Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis (programmed cell death), necrosis, and inflammationCaspases are essential in cells for apoptosis, or programmed cell death, in development and most other stages of adult life, and have been termed “executioner” proteins for their roles in the cell. Caspase 8 is a caspase protein, encoded by the CASP8 gene. It most likely acts upon caspase 3. CASP8 orthologs have been identified in numerous mammals for which complete genome data are availableThe CASP8 gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes composed of a prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. Caspase-8 is a member of the cysteine-aspartic acid protease (caspase) family, and is unique among caspases in that it has two opposing biological functions: cell survival and cell death. Caspase-8 promotes cell death by triggering the extrinsic pathway of apoptosis.

Conclusion

N del at −652 position in the promoter region of CASP8 gene is found to abolish the binding site for the transcriptional activator 1 (Sp1), thereby, resulting in a decreased expression of the CASP8 protein in lymphocytesFrequency of heterozygotes (ID) was elevated in controls (34%) compare with cases (22%), whereas the frequencies of homozygotes DD (17%) decreased in controls (0%). D allele frequency was found to be more in cases (0.25%) than in controls (0.17%) indicating that presence of D allele confers risk to development of CMLFrequency of deletion allele was elevated among the hematological and cytogenetic responders compared to that of minor responders indicating that this allele may not play in the progression of the disease.
Acknowledgment: This work was funded by department of Genetic, Osmania University,Hyderabad, India.

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