chronic myeloid leukemia falar

7/29/2019 Chronic Myeloid Leukemia Falar

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Chronic myeloid leukemia: Symptoms, Diagnosis and

treatment

The symptoms of this disease are:

Fatigue Easy bruising Weight loss Weakness Bleending of unknown origin High Fever Bone and joints pain Linfoadenopathy - swelling of the lymphatic nodes Splenomegaly swelling of the spleen Hepatomegaly sweeling of the liver Paleness

So, in order to diagnose CML there are some tests required:

A bone marrow biopsy, in which well look for hyperplasia ofthe granulopoietic tissue. That means an abnormal quantity ofwhite blood cells in the bone marrow, more specificallyeosinophils, basophils and blasts.A mild increase in basophils and eosinophils is very common andbecomes more prominent during the transition to the acceleratedphase of the disease.

An Hemogram, in which we will also look for a higher thannormal number of white blood cells.

A peripheral blood hemogram of a pacient with CML often showsanemia, thrombocytopenia (low number of platelets), hyperuricemia(high level of uric acid in the blood), which is a reflection of highbone marrow cellular turnover; elevated serum of Vitamin B-12Binding Protein (TC-I), increased mature granulocytes and normal


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lymphocyte counts, low score of Leukocyte Alkaline Phosphatase(LAP) enzyme.

The peripheral blood smear in patients with CML shows a typical

leukoerythroblastic blood picture, with circulating immature cellsfrom the bone marrow.

An other cytogenetic and molecular biology tests in which wesearch for chromosome alterations and identify/count theBCR/ABL transcripts.This way the mRNA transcripted from the BCR-ABL gene can bedetected, like the fluorescence in situ hybridization test (FISH),

the PCR (Polymerase Chain Reaction) test, the Southern Blottingtest, the Reverse Transciptase Polimerase Chain Reaction (RT-PCR) test and the Quantitative real-time Reverse TranscriptasePolimerase Chain Reaction (RQ-PCR) test. This last one is themost sensible test, although the RT-PCR test is the most used todiagnose this disease.

The FISH test uses labeled probes that are hybridized tometaphase chromosomes, and the hybridized probe is detected

with fluorochromes.This technique is a rapid and sensitive way of detecting recurringnumerical and structural abnormalities.After the bone marrow cells have grown through culture, theircycle is stopped in metaphase, so the chromosomes arecondensed. Then the cells are fixated and put on blade. A DNAprobe is labeled fluorescently and hybridized directly with thechromosomes on the blade. It is then possible to immediatelydetect fluorescent signals, through the fluorescence microscope.

The Treatment

The treatment of CML can be done through bone marrowtransplantation, through biological therapy and chemotherapyand through target therapy, which uses BCR-ABL tyrosine kinaseinhibitors.


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As the tyrosine kinase activity of the BCR-ABL proteins is knownto be essential to their transforming abilities, a specific inhibitor

of the ABL protein tyrosine kinase might be useful as a therapy

for CML and other BCR-ABL-positive leukaemias. This therapycan be divided according to whether or not the competitive

inhibition of ATP.

Imatinib is a drug used to fight CML. It is an example of aproduct with competitive inhibition of ATP, which competitivelyinhibit the binding of ATP to the tyrosine kinase domain of ABL,

preventing that way its phosphorylation of the substrates,blocking the activity of BCR-ABL protein and therefore inducingleukemic cell death.

Imatinib has revolutionized the treatment of CML, because it has ahigh level of activity and low toxicity. However, resistance toimatinib has become increasingly important.

Relapse during imatinib treatment is common and its due to anamplification and overexpression of the BCR-ABL gene and tomutations in the kinase domain of BCR-ABL that interfere withimatinib binding. It can also happen the failure to maintainappropriate concentrations of drug within the cell, for example byexcessive metabolism.

The Dasatinib is an ABL kinase inhibitor that differs fromimatinib because it can bind to both the active and inactive

conformations of the ABL kinase domain. Dasatinib also inhibitsa distinct spectrum of kinases that overlaps with the array of

kinases that imatinib inhibits. Since it has less stringent binding

requirements than does imatinib, dasatinib has activity against

many imatinib-resistant kinase domain mutations of BCR-ABL.

Dasatinib inhibited 18 of 19 imatinib-resistant BCR-ABL

mutations. The only exception is a single mutation deep within

the ATP-binding pocket of the ABL tyrosine kinase (T315I) that

confers a high degree of resistance to both drugs.


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Among drugs that act against the T315I mutant of BCR-ABL isthe MX-0457, an aurora kinase. This drug works by a differentmechanism of the former ones because it doesnt compete withthe ATP. This family of kinases is essential for the process control

during mitotic cell division. The MX-0457 is able to bind to ABL,leading to a substitution of an isoleucine for a threonine in the315 residue and inducing cell death.

Nilotinib, Bosutinib, DCC-2036, Ponatinib (AP24534) and AT9283are other drugs that are used on the treatment of CML, in case ofan Imatinib resistance.

chronic myeloid leukemia falar

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