Faculdade Medicina Universidade de Coimbra
Biologia Celular e Molecular II
2012-2013
Elaborated by:
José Duarte
Luís Oliveira
Pedro Pereira
Turma 9
PHILADELPHIA CHROMOSOME (Ph)
 Discovered in 1960 by Peter C.
Nowel and David Hungerford;
 First oncological gene documented;
 Advances in cytogenetics.
In site http://articles.philly.com/2010-09-29/news/24980608_1_chromosome-chronic-myeloid-leukemia-leukemia-cells
 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 http://www.medicinageriatrica.com.br/tag/cromossomo-filadelfia/
Normal Chromosomes
Chromosomes Break
Changed Chromosomes
Changed
Chromosome 9
Chromosome 9
Chromosome 22
Philadelphia
Chromosome
In site http://www.unesp.br/prope/projtecn/Saude/saude48a.htm
 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
Three distinct forms:
p190BCR/ABL
p210BCR/ABL
p230BCR/ABL
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
Chronic
Myelogenous
Leukemia (CML)
The philadelphia
chromosome is
present in 95% of
people with CML
p210BCR/ABL
Acute
Lymphoblastic
Leukemia (ALL)
Acute
Myelogenous
Leukemia (AML)
Acute
Lymphoblastic Ph chromosome
appears
45–60% in (ALL)
adult Leukemia
occasionally;
and 80%
in
25–30%
in adult
pediatric
cases
and 2–10%
in most common in
adults
p190BCR/ABL
pediatric
cases
p230BCR/ABL
Chronic myelogenous leukemia
 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. (Morales et al, 2010)
Acute lymphoblastic leukemia Ph (+)
- Thrombocytopenia;
- Leukocytopenia;
- Vulnerability to bruising, bleeding and
infections;
- Lymphadenopathy;
- Splenomegaly;
- Pain in the bones or joints.
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/
• PHILADELPHIA CHROMOSOME IDENTIFICATION:
– Peripheral blood and bone marrow samples submitted to:
 Kariotype analysis (gold standard)
 FISH





Southern Blotting
Traditional PCR
RT-PCR
RQ-PCR (high sensitivity)
Anchor-PET
CHROMOSOME
ALTERATIONS
BCR/ABL
transcripts
IDENTIFICATION
and/or
QUANTIFICATION
Karyotype Analysis
In site http://www.citogene.com.br/Citogenetica-De-Cancer.aspx
Fluorescent hybridization in situ
(FISH)
In site http://pt.wikipedia.org/wiki/Leucemia_mieloide_cr%C3%B4nica
Polymerase Chain Reaction (PCR)
In site http://www.scielo.br/scielo.php?pid=S0104-42301998000300015&script=sci_arttext






CHEMOTHERAPY
DONOR LYNPHOCYTE INFUSION
TARGET THERAPY
BIOLOGICAL THERAPY
SURGERY
HIGH DOSE CHEMOTHERAPY WITH STEM
CELLS TRANSPLANT
characteristic genetic
abnormality of CML:
Philadelphia
chromosome
protein BCR-ABL
tyrosine kinase
inhibitor of the
BCR-ABL tyrosine
kinase
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 http://the-medical-dictionary.com/imatinib_mesylate.htm
SECOND GENERATION TKI
DASATINIB
NILOTINIB
BOSUTINIB
DCC-2036
AP24534
AT9283
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• Douglas, H; Robert A. W. – Hallmarks of Cancer: next generation. Elsevier. March 4, 2001.
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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.
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•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
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• Knowles M., Selby P. Introduction to the Cellular and Molecular Biology of Cancer. 4 th ed. 2005, Oxford University
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