Download PDGFR - beta

KARRA C. PASONS
BIOL 445 – CANCER BIOLOGY
PRESENTATION
And its role in Leukemia
http://old.sinobiological.com/Platelet-derived-growth-factor/Structures-of-a-platelet-derived-growth-factor.jpg
PDGFRβ is a receptor tyrosine kinases
(RTK) that receives PDGF signals
https://www.withfriendship.com/images/i/44179/the-activation-of-pkc-is.jpg
There are multiple
PDGF ligands and
receptors and
dimer ligands
dimerize receptors
(Hoch – 2003)
PDGFβ mutants die
Perinatally with defects in
blood cells and the kidney
(Soriano – 1994)
(Soriano – 1994)
The transcription factor c-Myb is a
Downstream Target of PDGFβ
(Chen – 2007)
c-Myb concentration after treatment with
PDGF BB ligand
C-Myb inhibits apoptosis of
vascular smooth muscle cells
• Truncated PDGFRα
induces apoptosis
• c-Myb overrides the
apoptotic effects of
truncated PDGFRα
(Chen – 2007)
Chronic Myelomonocytic Leukemia
 CMML is a myelodyplastic syndrome
characterized by clonal myeloid proliferation
and progression into AML (acute myelogenous
leukemia)
 4 in a million people a year in USA
 9 out of 10 people are diagnoses at 60 years or
older
http://www.pubcan.org/images/lym4/thumb/lym4-03a.jpg
CMML is associated with Chromosome
Translocation t(5;12)(q33;p13) fusing tel
and PDGFRβ
Large arrow represents fused
chromosome
(Golub - 1994)
(Golub - 1994)
The HLH Domain Of Tel Is Fused To PDGFR
And Dimerizes Receptor Without Ligand!
http://www.uni-salzburg.at/uploads/RTEmagicP_DNA_transcription.jpg
Gleevec (Imatinib) is a small molecule
tyrosine kinase inhibitor that inhibits PDGFR
• Blocks kinase domain
• Binds to ATP binding
site when in inactive
state
• New mutations in
active site that inhibit
Imatinib binding
http://onlinelibrary.wiley.com/store/10.1111/febs.12163/asset/image_m/febs12163-toc-0001m.png?v=1&s=756f1b64ec5cb0ffc3ae3817777e1fc0e3080bf0
AMN107 is another tyrosine kinase inhibitor
developed to help deal with Gleevec
resistance
Table 4. Effects of AMN107 on characteristics of TEL-PDGFR- and FIP1L1-PDGFR-induced myeloproliferative disease
TEL-PDGFR
Placebo
TEL-PDGFR
AMN107
FIP1L1-PDGFR
Placebo
FIP1L1-PDGFR
AMN107
Mean
563.7
18.6
569.7
5.6
Standard deviation
96.0
8.8
88.2
2.3
Median
583.4
15.9
613.2
4.7
Range
459.3–648.3
10.9–33.5
452.8–659.2
4.0–9.6
3
5
5
5
Mean
802.5
350.0
731.8
88.0
Standard deviation
214.8
89.0
120.0
21.7
Median
800
340
700
100
Range
380–1130
250–470
575–880
50–100
8
8
5
5
Mean
1746.3
1492.5
1666.4
1128.0
Standard deviation
546.9
103.3
135.5
90.9
Median
1910
1535
1596
1090
Range
590–2410
1320–1590
1550–1830
1080–1290
8
8
5
5
WBC, 109/L
n
Spleen weight, mg
• Significantly lower
WBC count after
7 days in AMN107
treated mice
• P<0.05
n
Liver weight, mg
n
(Stover – 2005)
Summary
 PDGFRβ is a receptor tyrosine kinase found in
mesenchyme cells (eg. VSMC and myeloid cells)
 Causes activation of downstream transcription
activators such as c-myb
 tel-PDGFRβ translocation causes CMML by leading to
constitutively active PDGFRβ
 tel-PDGFRβ allows cells to escape cellular regulatory
pathways such as apoptosis
 Gleevec and AMN107 are small molecule inhibitors of
PDGFRβ
References

American Cancer Society, “Leukemia: Chronic Myelomonocytic” (2012 Mar. 21); Retrieved from
http://www.cancer.org/cancer/leukemia-chronicmyelomonocyticcmml/detailedguide/leukemia-chronicmyelomonocytic-what-is-it

Apperley, Jane F., et. al, “Response to imatinib mesylate in patients with chronic myeloproliferative diseases with
rearrangements of the platelet-derived growth factor receptor beta”, N Engl Med, Vol. 347 No. 7; (2002 Aug. 15)

Chen, Yitan, “The c-Myb functions as a downstream target of PDGF-mediated survival signal in vascular smooth
muscle cells” Biochemical and Biophysical Research Communications, Vol. 360, Issue 2,, Pg. 433-436 (2007, Aug. 24)

Cross, NCP and Reiter, A., “Tyrosine kinase fusion genes in chronic myeloproliferative diseases” Leukemia 16, 12071212 (2002)

Golub, Todd R., ”Fusion of PDGF Receptor β to a Novel ets-like Gene, tel in Chronic Myelomonocytic Leukemia with
t(5;12) Chromosomal Translocation” Cell, Vol. 77, 307-316. (1994, April 22)

Hoch, Renee V. And Soriano, Phillippe, ”Roles of PDGF in animal development”, Develpment 130, 4769-4784; (2003)

Soriano, Phillippe, “Abnormal kidney development and hematological disorders in PDGFβ-receptor mutant mice.
Genes and Development. ;(1996)

Stover, Elizabeth, H., et. al, “The small molecule tyrosine kinase inhibitor AMN107 inhibits TEL-PDGFRβ AND FIP1L1PDGFRα in vitro and in vivo” Blood Vol. 106 No. 9; (2005 Nov. 1)