KARRA C. PASONS BIOL 445 – CANCER BIOLOGY PRESENTATION.
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Transcript of KARRA C. PASONS BIOL 445 – CANCER BIOLOGY PRESENTATION.
PDGFRβ
Platelet Derived
Growth Factor
Receptor Beta
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
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 PDGFRAnd 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
http://onlinelibrary.wiley.com/store/10.1111/febs.12163/asset/image_m/febs12163-toc-0001-m.png?v=1&s=756f1b64ec5cb0ffc3ae3817777e1fc0e3080bf0
• Blocks kinase domain• Binds to ATP binding
site when in inactive state
• New mutations in active site that inhibit Imatinib binding
AMN107 is another tyrosine kinase inhibitordeveloped to help deal with Gleevec resistance
Table 4. Effects of AMN107 on characteristics of TEL-PDGFR- and FIP1L1-PDGFR-induced myeloproliferative disease
TEL-PDGFR TEL-PDGFR FIP1L1-PDGFR FIP1L1-PDGFR Placebo AMN107 Placebo AMN107
WBC, 109/L
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 n 3 5 5 5
Spleen weight, mg 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 n 8 8 5 5
Liver weight, mg 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 n 8 8 5 5
(Stover – 2005)
• Significantly lower WBC count after 7 days in AMN107 treated mice
• P<0.05
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-chronic-myelomonocytic-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, 1207-1212 (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 FIP1L1-PDGFRα in vitro and in vivo” Blood Vol. 106 No. 9; (2005 Nov. 1)