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Philadelphia Chromosome

Philadelphia Chromosome. Importance in the oncologic diagnosis. Faculdade Medicina Universidade de Coimbra Biologia Celular e Molecular II 2012-2013. Elaborated by : José Duarte Luís Oliveira Pedro Pereira Turma 9. Introduction. Philadelphia chromosome (Ph)

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Philadelphia Chromosome

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  1. Philadelphia Chromosome Importance in theoncologicdiagnosis Faculdade Medicina Universidade de Coimbra Biologia Celular e Molecular II 2012-2013 Elaboratedby: José Duarte Luís Oliveira Pedro Pereira Turma 9

  2. Introduction • Philadelphia chromosome(Ph) • Discoveredin 1960 by Peter C. Noweland David Hungerford; • Firstoncological gene documented; • Advances in cytogenetics. In site http://articles.philly.com/2010-09-29/news/24980608_1_chromosome-chronic-myeloid-leukemia-leukemia-cells

  3. Origin • Resultsfrom a reciprocaltranslocation t(9;22) (q34;q11) • Defectivechromosome 22 isdesignated Philadelphia Chromosome • Quimerical gene BCR-ABL isproduced In site http://www.medicinageriatrica.com.br/tag/cromossomo-filadelfia/

  4. origin Normal Chromosomes Chromosomes Break ChangedChromosomes Changed Chromosome 9 Chromosome 9 Philadelphia Chromosome Chromosome 22 In site http://www.unesp.br/prope/projtecn/Saude/saude48a.htm

  5. Fusion gene • Increases the tyrosine-kinase activity of ABL; • Active; doesn’t need activation by other cellular messaging proteins; • Activates some cell cycle-controlling proteins and enzymes, speeding up cell division; • Inhibits DNA repair; • Increased proliferation in response to growth factors; • Increased resistance to apoptosis, and alteration of their adhesion properties. In site http://www.biologyreference.com/Oc-Ph/Oncogenes-and-Cancer-Cells.html

  6. Fusion gene Three distinct forms: p190BCR/ABL p210BCR/ABL p230BCR/ABL Leucemia

  7. leukemia Malignant tumor of bone marrow hematopoietic cells, that leads to the accumulation of the blast cells throughout the body. In site http://www.cancer.gov/cancertopics/pdq/treatment/CML/Patient/page1

  8. Cancers related to Philadelphia Chromosome Acute Myelogenous Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myelogenous Leukemia (CML) The philadelphiachromosome is present in 95% of people with CML p210BCR/ABL 45–60% in adult and 80% in pediatric cases p190BCR/ABL Ph chromosome appears occasionally; most common in adults p230BCR/ABL Acute Lymphoblastic Leukemia (ALL) - 25–30% in adult and 2–10% in pediatric cases

  9. ClinicalPresentation Chronicmyelogenousleukemia - Thrombocytopenia; - Leukocytopenia; -Vulnerability to bruising, bleeding and infections; - Lymphadenopathy; - Splenomegaly; - Pain in the bones or joints. AcutelymphoblasticleukemiaPh (+) • Chronicphase(4-6 years): - Asymptomatic; - Thrombocytosis; - Leukocytosis; - Blast cell count less than 10%. • Acceleratedphase(18 months): - Splenomegaly; - Thrombocytopenia; - Leukocytosistreatmentresistant; -increasedblastcells (10-30%) in peripheral blood and bone marrow; - Clonalevolution. • Blastic /acutephase(survival 2-4mounths) - ≥ 30% blast cells in bone marrow; - More resistant to treatment. (Moralesetal, 2010)

  10. Diagnosis clinically oriented: Splenomegaly Hemogram (blasts, basophiles, eosinophils) Myelogram Bone marrow biopsy Referral to molecular and cytogenetic tests In site http://iahealth.net/acute-myeloid-leukemia/

  11. visualizationtechniques • Philadelphia chromosome identification: • Peripheral blood and bone marrow samples submitted to: • Kariotype analysis (gold standard) • FISH Chromosome Alterations • Southern Blotting • Traditional PCR • RT-PCR • RQ-PCR (high sensitivity) • Anchor-PET BCR/ABL transcripts identification and/or quantification

  12. visualizationtechniques KaryotypeAnalysis In site http://www.citogene.com.br/Citogenetica-De-Cancer.aspx

  13. visualizationtechniques Fluorescenthybridizationin situ (FISH) In site http://pt.wikipedia.org/wiki/Leucemia_mieloide_cr%C3%B4nica

  14. visualizationtechniques PolymeraseChainReaction (PCR) In site http://www.scielo.br/scielo.php?pid=S0104-42301998000300015&script=sci_arttext

  15. treatment Chemotherapy DonorLynphocyteinfusion Target Therapy BiologicalTherapy Surgery High Dose Chemotherapy with stem cells transplant

  16. Target Therapy • inhibitor of the • BCR-ABL tyrosine kinase

  17. Target Therapy Imatinib Mesylate Excelenttherapeuticeficiency Lowtoxicity Blocks ATP binding site of BCR-ABL Shorttimesideeffects Resistance to imatinib • Philadelphia chromosomewastheonsetoftargettherapyincancer In site http://the-medical-dictionary.com/imatinib_mesylate.htm

  18. Target Therapy SecondGeneration TKI Dasatinib Nilotinib Bosutinib DCC-2036 AP24534 AT9283

  19. References Almeida A, Castro I, Coutinho J, Guerra L, Marques H, Pereira AM. Recomendações para o Diagnóstico, Tratamento e Monitorização da Leucemia Mielóide Crónica. Acta MedPort 2009; 22: 537-544 Cayuela J-M, Macintyre E, Darlington M, Abdelali RB, Fund X, Villarese P, Tulliez M, Raffoux E, Sigaux F, Réa D, and Seror V. Cartridge-based automated BCR-ABL1 mRNA quantification: solving the issues of standardization, at what cost?. Haematologica 2011;96(5):664-671. Chauffaille ML. Análise citogenética e FISH no monitoramento da LMC em tratamento com inibidores da tirosinoquinase. Rev. Bras. Hematol. Hemoter. 2008, 30 (Imagem FIsh) Douglas, H; Robert A. W. – Hallmarks of Cancer: next generation. Elsevier. March 4, 2001. Druker B. J. [et al]. Activity of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase In the Blast Crisis of Chronic Myeloid Leukemia And Acute Lymphoblastic Leukemia With the Philadelphia Chromosome. N Engl J Med, Vol. 344, No. 14 April 5, 2001. Funke, V. et al (2010). Leucemia Mielóide Crónica e outra doenças mieloprofilerativas crónicas. Revista Brasileira de Hematologia e Hemoterapia. 32 (Supl.1):71-90. Goodsell D. S. The Molecular Perspective: c-Abl Tyrosine Kinase. The Oncologist 2005;10:758–759 Grando AC; Wagner SC. Avaliação laboratorial da doença residual mínima na leucemia mielóide crônica por Real-Time PCR. J BrasPatolMedLab. 2008, 44(6): 433-440 Griffiths, Anthony J. F. [et al]. Introdução à genética. 8ªedição. Rio de Janeiro: Guanabara-Koogan, 2006. Guttmacher A. E., Collins F. S. Molecular Diagnosis of the Hematologic Cancers. N Engl J Med 2003;348:1777-85. Hanahan D., Weinberg R. A. Hallmarks of Cancer: The Next Generation. Cell 144, March 4. Elsevier Inc, 2011. Harrison – Medicina Interna. 17ª Edição, vol.I:683-686. Hughes T, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. BLOOD. 2006, 108(1) 28-37 Knowles M., Selby P. Introduction to the Cellular and Molecular Biology of Cancer. 4 th ed. 2005, Oxford University Press. 189-193, 203-204, 219-226, 2005 Koo, H. (2011). Philadelphia Chromossome-Positive Acute Lymphoblastic Leukemia in Childhood. Korean J Pediatr. 54 (3): 106-110.

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