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Philadelphia Chromosome Importance in the oncologic diagnosis

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Presentation on theme: "Philadelphia Chromosome Importance in the oncologic diagnosis"— Presentation transcript:

1 Philadelphia Chromosome Importance in the oncologic diagnosis
Faculdade Medicina Universidade de Coimbra Biologia Celular e Molecular II Elaborated by: José Duarte Luís Oliveira Pedro Pereira Turma 9

2 Introduction Philadelphia chromosome (Ph)
Discovered in 1960 by Peter C. Nowel and David Hungerford; First oncological gene documented; Advances in cytogenetics. A descoberta do crom. Filadelfia conferio à citogenética um papel importante na hematologia, possibilitando o diagnóstico da LMC. In site

3 Origin 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 Philadelphia Chromosome
origin Normal Chromosomes Chromosomes Break Changed Chromosomes Changed Chromosome 9 Chromosome 9 Philadelphia Chromosome Chromosome 22 In site

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

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

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

8 Cancers related to Philadelphia Chromosome Chronic Myelogenous Leukemia (CML) Acute Lymphoblastic Leukemia (ALL) Acute Myelogenous Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) - 25–30% in adult and 2–10% in pediatric cases The philadelphia chromosome 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

9 Clinical Presentation Acute lymphoblastic leukemia Ph (+)
Chronic myelogenous leukemia Acute lymphoblastic leukemia Ph (+) 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. (Morales et al, 2010)

10 Diagnosis clinically oriented: Splenomegaly Hemogram
(blasts, basophiles, eosinophils) Myelogram Bone marrow biopsy Referral to molecular and cytogenetic tests In site

11 visualization techniques
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 visualization techniques
Karyotype Analysis In site

13 visualization techniques
Fluorescent hybridization in situ (FISH) In site

14 visualization techniques
Polymerase Chain Reaction (PCR) In site

15 treatment Chemotherapy Donor Lynphocyte infusion Target Therapy
Biological Therapy Surgery High Dose Chemotherapy with stem cells transplant

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

17 Philadelphia chromosome was the onset of target therapy in cancer
Imatinib Mesylate Excelent therapeutic eficiency Low toxicity Blocks ATP binding site of BCR-ABL Short time side effects Resistance to imatinib Philadelphia chromosome was the onset of target therapy in cancer In site

18 Target Therapy Second Generation 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 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, 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 Bras Patol Med Lab. 2008, 44(6): 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: 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: 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 , , , 2005 Koo, H. (2011). Philadelphia Chromossome-Positive Acute Lymphoblastic Leukemia in Childhood. Korean J Pediatr. 54 (3):

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