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Philadelphia Chromosome

philadelphia chromosome, cancer

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27 views

Philadelphia Chromosome

philadelphia chromosome, cancer

Uploaded by

Isha
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PPTX, PDF, TXT or read online on Scribd
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PHILADELPHIA

CHROMOSOME
AS A
BIOMARKER PRESENTED BY:

AMARJEET KUMAR (BTB/17/107)


ANUSHREYA (BTB/17/108)
MADHUMITA DEY (BTB/17/109)
HEMANT KUMAR JHA (BTB/17/111)
WHAT IS A BIOMARKER?
• Biomarkers are substances or molecules that is indicative of the
presence of cancer in the body [1].

• It is secreted by tumour or a specific response of the body to the


presence of cancer [1].

• Applications and uses of Biomarkers are in Diagnostic, Prognostic


and Predictive [1].

• Some examples of Biomarkers:


- HER-2/ neu for Breast Cancer
- EGFR for colorectal cancer
- Philadelphia Chromosome (BCR/ABL1) for Leukemia
1. Nalini Kanta Sahoo & Madhusmita
Sahu, 2019
WHAT IS PHILADELPHIA
CHROMOSOME?
• Philadelphia Chromosome or
Philadelphia translocation (Ph) is a
specific genetic abnormality in
Chromosome 22 of leukemia cancer cells
(specifically Chronic myeloid leukemia)
[2].

• Philadelphia chromosome is formed as a


consequence of reciprocal
translocation between the
Chromosome 9 and Chromosome 22,
resulting in the fusion of Abelson
Murine Leukemia (ABL1) from
2. Jessica Wapner & Robert A. Weinberg,
Chromosome 9 to Break Point Cluster 2014
region (BCR) gene on Chromosome 22, 3. Daniel W. Sherbenou & Brian J. Druker,
2007
called as BCR-ABL1 fusion gene [3].
BCR, ABL1 and BCR-ABL1 gene
BCR gene:
• It is known as Breakpoint Cluster Region.
• This region is responsible for homotetramerization of BCR-ABL1 molecule
and necessary for its transforming potential [4].

ABL1 gene:
• It is known as Abelson Murine Leukemia gene [5].
• Proto-oncogene encodes a cytoplasmic and nuclear protein tyrosine kinase
that has been implicated in processes of cell differentiation, cell division, cell
adhesion and stress response [6].

4. Ali G Turhan, 2008


5. Elias Jabbour and Hagop
Kantarjian, 2018
6. UniprotKB, 2020
BCR-ABL1 fusion gene:

• This fusion gene, BCR-ABL1 encodes an unregulated, cytoplasm-


targeted tyrosine kinase that allows the cells to proliferate without being
regulated by cytokines. This in turn, allows cells to become cancerous.

• This disruption influences leukemogenesis by creating a cytokine-


independent cell cycle with aberrant apoptotic signals in response to
cytokine withdrawal [5].

• BCR-ABL1 is a constitutively active tyrosine kinase that promotes growth


and replication through downstream signalling pathways [5].

• BCR-ABL1 gene activity can be inhibited by various small molecules such


as imatinib mesylate, which occupies the tyrosine kinase domain and
inhibits BCR-ABL’s influence in cell cycle. 5. Elias Jabbour and Hagop
Kantarjian, 2018
MOLECULAR BASIS OF PHILADELPHIA
CHROMOSOME
• Translocation of BCR and ABL1 gene results in an BCR-ABL1 oncogenic gene
fusion that can be found on shorter derivative Chromosome 22 [7].

• Three common forms of BCR-ABL1 , depending on the exact point on


Chromosome 22 where the breakpoint occurs. When large amounts of BCR
gene are included in fusion gene protein, the molecular weights is
approximately 210kDa (associated with Chronic myeloid Leukemia) referred
to as p210. The alternate forms include p190 (associated with B-cell acute
lymphoblastic leukemia) and p230 (associated with chronic myelogenous
leukemia, associated with neutrophilia and thrombocytosis) [7][8].

• The ABL1 gene of Chromosome 9 juxtaposed onto the BCR gene of


Chromosome 22, coding for a hybrid protein, a tyrosine kinase signalling
protein that is “always on”, causing the cells to divide
2. Jessicauncontrollable
Wapner & Robert A. by
interrupting the stability of the genome and impairing
Weinberg, various
2014 signalling
7. D E Sabath, 2013
pathways governing the cell cycle [2]. 8. Advani & A S Pendergast, A. M.,
2002
ROLE IN LEUKEMIA:

• BCR-ABL1 fusion gene and protein encoded by the Philadelphia


Chromosome affects multiple signalling pathways that directly
affect apoptotic potential, cell division rate, and different stages of
cell cycle to achieve unchecked proliferation characteristic of CML
and AML.

• Multiple signalling pathways include:


i) JAK/STAT Pathway
ii) Ras/MAPK Pathway
iii) DNA Binding and Apoptosis
i) JAK/STAT Pathway:
• The human genome codes for 4 JAK (JAK1, JAK2, JAK3, Tyrosine Kinase) and
7 STAT (1,2,3,4,5A,5B,6) proteins which mediate more than 30 cytokine
receptor that belong to the cytokine receptor superfamily[9].

• JAK2 phosphorylates the BCR-ABL1 fusion proteins at Y177 and stabilizes


the fusion protein, strengthening tumorigenic cell signalling[10].

• JAK2 mutations have been shown to be central to myeloproliferative


neoplasm and JAK kinases plays a central role in driving heamatological
malignancies[10].

• JAK/STAT Pathway promotes growth of leukemic cells exhibiting Ph


chromosome and BCR-ABL1 tyrosine kinase activity[10].

• BCR-ABL upregulation of JAK/STAT signalling plays an important role in


9. Warsch W & Walz
maintaining leukemic cell growth and division[9]. C, 2013
10. Oliver Hantschel,
2015
ii) Ras/MAPK Pathway:
• This pathway relays signals to nuclear transcription factors and plays a role in
governing cell cycle control and differentiation[12].

• The MAPK cascade is a key signalling pathway that regulates diverse cellular functions
including cell proliferation, survival, differentiation, angiogenesis and migration[11].

• In Ph-chromosome-containing cells, the BCR-ABL tyrosine kinase activates the


pathway, which results in unregulated cell proliferation via gene transcription in the
nucleus[13].

• BCR-ABL fusion cell also exhibit constitutively high levels of activated Ras bound to
GTP, activating a Ras-dependent signalling pathway which has been shown to inhibit
apoptosis downstream of BCR-ABL[13].

• Dysregulated signalling through the Ras pathway is often result of genetic alteration in
critical components in this pathway as well as mutations at upstream growth
receptors[14].
11. Thomas Knight,
• This pathway is also implicated in overexpression of osteopontin(OPN), 2014which is
important for maintenance of hematopoietic stem cell niche, which indirectly12. L S Steelman, 2004
influences
13. G Bandyopadhyay,
iii) DNA Binding and Apoptosis

• The c-ABL gene in wild type cells is implicated in DNA binding, which affects such
processes as DNA Transcription, repair, apoptosis, and other processes underlying the
cell cycle[15].

• c-ABL phosphorylates HIPK2, a serine/threonine kinase, in response to DNA damage


and promotes apoptosis in normal cells[15].

• BCR-ABL have a pro-apoptotic expression profile by increased levels of p53, p21, Bax.
The function of these pro-apoptotic proteins, however is impaired, and apoptosis is not
carried out of these cells[16].

• The IKAROS gene is critical to Pre B-cell receptor-mediated cell cycle arrest in ALL cells
positive for Ph, which when impaired provides a mechanism for unchecked cell cycle
progression and proliferation of defective cells as encouraged by BCR-ABL tyrosine
kinase signalling[17]. 15. BA Burke and M Carroll, 2010
16.Z Kang, 2011
17.Sanjive Qazi & Fatih M Uckun,
2013
Diagnosis:
• by Metaphase Cytogenetics[7]
• FISH ( fluorescence in situ Hybridisation)[7]

Prognostic Scoring System:


Sokal, Hasford and EUTOS system

A tabular representation of Prognostic Scoring


7. D E Sabath, System. Source: Kendra Sweet et. al ., 2013
2013
Therapy:

Credit: Santos et. al. , 2011


1) Tyrosine Kinase Inhibitors (TKI)[5]:
Imanitib
. :
• First Tyrosine Kinase Inhibitor
• It acts via competitive inhibition at the ATP-
binding site of BCR-ABL1 oncoprotein, which
results in the inhibition of phosphorylation of
proteins involved in signal transduction.

Dasatinib:
• Oral, second generation TKI that is 350 times more
potent than imanitib in vitro.
• It also inhibits the Src Family of Kinases, which may
be important in blunting critical cell signalling
Credit: Santos et. al. , 2011
pathways
Nilotinib:
• It is a structural analog of Imanitib.
• It initially demonstrated the ability to induce hematologic and cytogenetic responses
in patients who had failed Imanitib.
5. Elias Jabbour and Hagop Kantarjian,
2018
Bosutinib:
• It is a potent dual Src/ABL kinase inhibitor.
• It is the first drug approved for adults with CML resistant and/or intolerant to prior
therapy

Axitinib:
• It is a drug used to treat renal cell carcinoma, but has shown to be effective at
inhibiting the ABL kinase
activity in patients with BCR-ABL1.

Nilotinib + Ruxolitinib:
• Combination therapies have shown success in suppressing resistance by targeting
the JAK/STAT and
BCR- ABL stages simultaneously.

Omacetaxine mepesuccinate[19]:
• Omacetaxine, a protein synthesis inhibitor, is indicated in the US for the treatment
of patients with
chronic (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) with
resistance and/or
5. Elias Jabbour and Hagop
intolerance to two or more tyrosine kinase inhibitors. Kantarjian, 2018
19. Arnaud Gilles et. al ., 2020
20. American Society of Clinical
THANK YOU

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