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Cell Signaling and CML

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alejandra lopez

on 28 November 2012

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Transcript of Cell Signaling and CML

How cells are able to communicate with each other by signals and how they interpret the signals received Cell Signaling It is the process by which a signal on a cell's surface is converted into a specific cellular response in a series of steps. What is it? How do cells communicate? Cells communicate by signals sent from other cells that they then traduce to trigger a specific cellular response Through Signal Transduction Pathway Stages Types of pathways Reception Transduction Response Reception is the detection of the signal molecule by the target cell, which senses it when it binds to the receptor protein at the cell's surface. * The signal molecule is a ligand, which is a molecule that has the capacity to bind with another. The binding of the signal molecule changes the shape of the receptor protein, initiating the transduction process. This stage converts the signal received to a form that can trigger a specific response. Transduction can occur in one step or in a sequence of changes in different molecules. The proteins along the way are usually called "relay molecules." In the third stage, the transduced signal triggers a specific cellular response. Chronic Myelogenous Leukemia (CML) It's effect on G-Protein-Linked Receptors It is a membrane receptor that works with the help of a G protein Receptor Tyrosine Kinase A receptor tyrosine kinase can trigger more than one signal transduction pathway at once. * A protein kinase is an enzyme that phosphorylates a molecule Ion Channel Receptors It is a type of membrane receptor in which a region acts as a gate when the receptor changes shape. When the signal molecule binds to the receptor protein, the gate opens allowing or blocking a flow of ions into the cell. Once the ligand dissociates the gate closes up again. Types of Cell Signaling Local Signaling Long-distance signaling Direct contact Signaling Paracrine Signaling Synaptic Signaling A secreting cell acts on nearby target cell by releasing molecules into the extracellular fluid. A nerve cell releases neurotransmitter molecules into a synapse, stimulating the target cell. Hormonal Signaling Specialized endocrine cells secrete hormones into body fluid, often the blood. Hormones can reach virtually all body cells. Cell junctions Cell-cell Recognition Plasmodesmata Gap Junctions Both animal and plant cells have cell junctions that allow molecules to pass through the cells without crossing the plasma membrane. Between animal cells Between plant cells Two cells in an animal communicate by interactions between molecules protruding from their surface. Second messengers and their role in signal transduction Cyclic AMP (cAMP) Calcium Ions An enzyme in the membrane adenylyl cyclase converts ATP to cAMP in response to an extracellular signal. The cAMP broadcasts the signal to the cytoplasm. The immediate effect of the cAMP is the activation of a serine/threonine kinase called "protein kinase A." It is more widely used as a second messenger than cAMP. Increasing the concentration of Ca2+ causes different responses in the cells. In animal cells it can cause muscle contraction, secretion of certain substances, and cell division. What is it? Chronic myeloid leukemia is a cancer of the bone marrow and blood. CML is usually diagnosed in its chronic phase when treatment is very effective for most patients. . It typically affects middle-aged individuals. Uncommonly, the disease occurs in younger individuals. Younger patients may present with a more aggressive form of CML, such as in accelerated phase or blast crisis. Uncommonly, CML may appear as a disease of new onset in elderly individuals. What causes it? The DNA removed from chromosome 9 contains most of the proto-oncogene designated c-ABL. The break in chromosome 22 occurs in the middle of a gene designated BCR. The resulting Philadelphia chromosome has the 5' section of BCR fused with most of c-ABL. In most cases of CML, the leukemic cells share a chromosome abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal translocation between one chromosome 9 and one chromosome 22. This translocation is designated t(9;22). It results in one chromosome 9 longer than normal and one chromosome 22 shorter than normal. The latter is called the Philadelphia chromosome and designated Ph1. •Chronic: a slow-growing condition that doesn't go away. •Myelogenous: related to the bone marrow, the spongy tissue that fills the large bones and makes blood cells. •Leukemia: a cancer of the blood cells, mainly white blood cells. Background: How CML originates Normally, blood cells are produced in the bone marrow. When your body needs them more, it makes them in a controlled way. All blood cells start as the same type of cell, called a stem cell. This earliest stem cell then develops into either a myeloid stem cell or a lymphoid stem cell. In chronic myeloid leukemia (CML), it is the granulocyte white blood cells that are cancerous. What are blasts? New, immature blood cells of any type are called blasts. Some blasts stay in the bone marrow to mature. Some travel through the blood system to other parts of the body before they mature. In CML, the disease can enter a phase where it suddenly begins to develop more quickly. There is a sudden growth of leukemia cells, with a lot of blasts in the bone marrow and blood. How CML affects the system White blood cells help to fight infection. So if you have abnormal white blood cells, you have less protection against infection. You may get a lot of infections and they may be difficult to get rid of.
When you have too many white blood cells, they take up more room in the bone marrow than normal. So there is not enough space for making red blood cells and platelets. Red blood cells carry oxygen round the body. If there are not have enough of these, the person will be tired and breathless.
Platelets are vital for normal blood clotting. If you have too few platelets, you will have bleeding problems such as nosebleeds or a fine rash of red spots caused by bleeding into the skin. How people develop the disease Although researchers know what genes are involved in the development of CML, they do not yet know why some people get it and others do not. Some causes may be: Radiation
Radiation can increase risk to some extent because atomic bomb survivors had an increased risk of leukemia. Use of radiotherapy for another cancer in the past could increase your risk of developing CML. But the risk is very small, compared to the benefit of the radiotherapy in treating the cancer. Low immunity
An analysis of published studies has shown that people with low immunity due to HIV or AIDS are 3 times more likely to develop leukemia than the general population. People who take drugs that lower their immunity after an organ transplant are twice as likely to develop leukemia. Ulcerative colitisOne study showed that people with the inflammatory bowel condition, ulcerative colitis, have almost double the risk of myeloid leukemia compared to the general population. Using pesticides at workA review looked at published evidence for men exposed to pesticides as part of their work (for example, farmers or agricultural workers). The review showed that the men had a 40% increase in their CML risk compared to the general population. BenzeneContact with a type of chemical called benzene for some years may increase CML risk. Benzene is one of the chemicals in petrol. It is also a solvent used in the rubber industry. Body weight
A combined review of 4 previously published studies showed that the risk of CML is increased by about a quarter for people who are overweight or obese, compared to people with a healthy body weight. Cell Signaling and CML The fusion protein BCR/ABL produced by the Philadelphia chromosome activates continuesly the cytosolic tyrosine kinase ABL that normally would be activated only when the cell is stimulated by a growth factor. The result: chronic myelogenous leukemia.
It is a receptor tyrosine kinases pathway. A, BCR-ABL signaling pathways activated in CML. Dimerization of BCR-ABL triggers autophosphorylation events that activate the kinase and generate docking sites for intermediary adapter proteins such as GRB2. BCR-ABL–dependent signaling facilitates activation of multiple downstream pathways that enforce enhanced survival, inhibition of apoptosis, and perturbation of cell adhesion and migration. Symptoms Chronic myelogenous leukemia is grouped into several phases:
•Blast crisis
The chronic phase can last for months or years. The disease may have few or no symptoms during this time. Most people are diagnosed during this stage, when they are having blood tests done for other reasons.
The accelerated phase is a more dangerous phse. Leukemia cells grow more quickly. Common symptoms include fever (without infection), bone pain, and a swollen spleen.
Blast Crisis: some symptoms may include
Infection due to bone marrow failure
Excessive sweating (night sweats)
Pressure under the lower left ribs from a swollen spleen
Rash - small pinpoint red marks on the skin
Weakness Treatments Drugs and Medicines •Dasatinib (Sprycel) and nilotinib (Tasigna): Dasatinib and nilotinib are two additional FDA-approved drugs that, like imatinib, are taken in pill form and treat CML by blocking the gene that causes cells to grow and divide. Both drugs, especially nilotinib, have been shown to be more effective than imatinib for some patients when used as initial therapy.
•Ponatinib: A new drug called ponatinib may soon be approved by the FDA. Ponatinib has shown promise for patients whose CML has relapsed or progressed, or who cannot tolerate treatments that are currently approved. •Gleevec: Imatinib mesylate, taken as a daily pill, has been the standard treatment for people newly diagnosed with CML. The first in a series of ‘targeted’ therapies for CML, imatinib works by shutting down the protein that causes CML cells to grow and divide. In eight out of 10 patients treated with imatinib, the Ph chromosome disappears completely. Gleevec is an inhibitor of specific tyrosine kinases that targets platelet-derived growth factor (PDGF) receptor.The kinase in effect prevents the formation of a product formed by the fusion of PDGF and Philadelphia (Ph) chromosome (expressed in CML). Stem cell transplantation is the only treatment that provides a potential cure for CML. A patient receives high doses of chemotherapy to destroy the bone marrow along with the leukemia cells in the body, and suppress the immune system. This is followed by an infusion of healthy, blood-forming stem cells donated by another person who has a nearly identical tissue type (either a family member or an unrelated donor). Chemotherapy may also be used to stop or slow the growth of cancer cells before stem cell transplantation. Targeted therapy uses drugs to identify and attack the cancer cells without hurting the normal cells. These drugs, called tyrosine kinase inhibitors, target the cancer cells in CML and may be used as the first treatment for patients with an early phase CML. Bone marrow transplant can be an option for some people whose CML advances or if multiple medicines have failed. To be eligible for a transplant, you need a well-matched donor—ideally a close relative like a brother or sister. Talk with your doctor about the potential benefits and risks of this treatment. Because the risks associated with bone marrow transplants increase with age, this procedure is usually recommended only for younger patients who have already tried various other treatments. Biological therapies harness your body's immune system to help fight cancer. The biological drug interferon is a synthetic version of an immune system cell. Interferon may help reduce the growth of leukemia cells. Interferon may be an option if other treatments don't work or if you can't take other drugs, such as during pregnancy. Side effects of interferon include fatigue, fever, flu-like symptoms and weight loss.
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