KARRA C. PASONSBIOL 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

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 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)