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
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