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Faculdade Medicina Universidade de Coimbra Biologia Celular e Molecular II 2012-2013 Elaborated by: José Duarte Luís Oliveira Pedro Pereira Turma 9.

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Presentation on theme: "Faculdade Medicina Universidade de Coimbra Biologia Celular e Molecular II 2012-2013 Elaborated by: José Duarte Luís Oliveira Pedro Pereira Turma 9."— Presentation transcript:

1 Faculdade Medicina Universidade de Coimbra Biologia Celular e Molecular II Elaborated by: José Duarte Luís Oliveira Pedro Pereira Turma 9

2 In site P HILADELPHIA CHROMOSOME (Ph) Discovered in 1960 by Peter C. Nowel and David Hungerford; First oncological gene documented; Advances in cytogenetics.

3 Results from a reciprocal translocation t(9;22) (q34;q11) Defective chromosome 22 is designated Philadelphia Chromosome Quimerical gene BCR-ABL is produced In site

4 Chromosome 9 Chromosome 22 Normal Chromosomes Chromosomes Break Changed Chromosomes Philadelphia Chromosome Changed Chromosome 9 In site

5 Increases the tyrosine-kinase activity of ABL; Active; doesnt 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

6 Three distinct forms: p190BCR/ABL p210BCR/ABL p230BCR/ABL

7 Malignant tumor of bone marrow hematopoietic cells, that leads to the accumulation of the blast cells throughout the body. In site

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

9 Chronic phase (4-6 years): - Asymptomatic; - Thrombocytosis; - Leukocytosis; - Blast cell count less than 10%. Accelerated phase (18 months): - Splenomegaly; - Thrombocytopenia; - Leukocytosis treatment resistant; - increased blast cells (10-30%) in peripheral blood and bone marrow; - Clonal evolution. Blastic /acute phase (survival 2-4mounths) - 30% blast cells in bone marrow; - More resistant to treatment. - Thrombocytopenia; - Leukocytopenia; - Vulnerability to bruising, bleeding and infections; - Lymphadenopathy; - Splenomegaly; - Pain in the bones or joints. Chronic myelogenous leukemia Acute lymphoblastic leukemia Ph (+) (Morales et al, 2010)

10 CLINICALLY ORIENTED : Splenomegaly Hemogram (blasts, basophiles, eosinophils) Myelogram Bone marrow biopsy R EFERRAL TO MOLECULAR AND CYTOGENETIC TESTS In site

11 P HILADELPHIA CHROMOSOME IDENTIFICATION : P HILADELPHIA CHROMOSOME IDENTIFICATION : – Peripheral blood and bone marrow samples submitted to: Southern Blotting Traditional PCR RT-PCR RQ-PCR (high sensitivity) Anchor-PET Southern Blotting Traditional PCR RT-PCR RQ-PCR (high sensitivity) Anchor-PET Kariotype analysis (g old standard) FISH Kariotype analysis (g old standard) FISH C HROMOSOME A LTERATIONS BCR/ABL transcripts IDENTIFICATION and/or QUANTIFICATION

12 Karyotype Analysis In site

13 In site Fluorescent hybridization in situ (FISH)

14 In site Polymerase Chain Reaction (PCR)

15

16 characteristic genetic abnormality of CML: Philadelphia chromosome protein BCR-ABL tyrosine kinase inhibitor of the BCR-ABL tyrosine kinase inhibitor of the BCR-ABL tyrosine kinase

17 In site P HILADELPHIA CHROMOSOME WAS THE ONSET OF TARGET THERAPY IN CANCER

18

19 Almeida A, Castro I, Coutinho J, Guerra L, Marques H, Pereira AM. Recomendações para o Diagnóstico, Tratamento e Monitorização da Leucemia Mielóide Crónica. Acta Med Port 2009; 22: 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): Chauffaille ML. Análise citogenética e FISH no monitoramento da LMC em tratamento com inibidores da tirosino quinase. Rev. Bras. Hematol. Hemoter. 2008, 30 (Imagem FIsh) Douglas, H; Robert A. W. – Hallmarks of Cancer: next generation. Elsevier. March 4, 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, Funke, V. et al (2010). Leucemia Mielóide Crónica e outra doenças mieloprofilerativas crónicas. Revista Brasileira de Hematologia e Hemoterapia. 32 (Supl.1): 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 Bras Patol Med Lab. 2008, 44(6): Griffiths, Anthony J. F. [et al]. Introdução à genética. 8ªedição. Rio de Janeiro: Guanabara-Koogan, Guttmacher A. E., Collins F. S. Molecular Diagnosis of the Hematologic Cancers. N Engl J Med 2003;348: Hanahan D., Weinberg R. A. Hallmarks of Cancer: The Next Generation. Cell 144, March 4. Elsevier Inc, Harrison – Medicina Interna. 17ª Edição, vol.I: 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) Knowles M., Selby P. Introduction to the Cellular and Molecular Biology of Cancer. 4 th ed. 2005, Oxford University Press , , , 2005 Koo, H. (2011). Philadelphia Chromossome-Positive Acute Lymphoblastic Leukemia in Childhood. Korean J Pediatr. 54 (3):


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