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Gene Expression and Serum Cytokine Profiling of Low Stage CLL Identify WNT/PCP, Flt-3L/Flt-3, and CXCL9/CXCR3 as Regulators of Cell Proliferation, Survival, and Migration

  1. Daruka Mahadevan dmahadevan{at}azcc.arizona.edu1
  2. James Choi jchoi{at}azcc.arizona.edu2
  3. Laurence Cooke lcooke{at}azcc.arizona.edu1
  4. Bram Simons bsimons{at}tsz.nl3
  5. Christopher Riley cjriley{at}email.arizona.edu1
  6. Thomas Klinkhammer tklinkhammer{at}azcc.arizona.edu1
  7. Rohit Sud rohit{at}gmail.com4
  8. Sirisha Maddipoti smaddipoti{at}azcc.arizona.edu1
  9. Sean Hehn shehn{at}hemonc.org5
  10. Harinder Garewal hgarewal{at}azcc.arizona.edu1
  11. Catherine Spier cspier{at}email.arizona.edu6
  1. 1Department of Hematology/Oncology, Arizona Cancer Center, Tucson, AZ 85724, USA
  2. 2Department of Hematology/Oncology, Hematology Oncology Associates, Phoenix, AZ 85012, USA
  3. 3Department of Hematology/Oncology, Radboud University Nijmegen Medical Center, Tilburg, Netherlands Medicine, 6500 HB Nijmegen, The Netherlands
  4. 4University of Rochester Medical Center, Rochester, NY 14642, USA
  5. 5Department of Hematology/Oncology, Hematology Oncology Associates, PC, Medford, OR 97504, USA
  6. 6Department of Pathology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA

Abstract

Gene expression profiling (GEP) of 8 stage 0/I untreated Chronic Lymphocytic Leukemia (CLL) patients showed over-expression of Frizzled 3 (FZD3)/ROR-1 receptor tyrosine kinase (RTK), FLT-3 RTK and CXCR3 G-protein coupled receptor (GPCR). RT-PCR of 24 genes in 21 patients of the WNT pathway corroborated the GEP. Transforming growth factorββ, fibromodulin, TGFβRIII and SMAD2 are also over-expressed by GEP. Serum cytokine profiling of 26 low stage patients showed elevation of IFNγ, CSF3, Flt-3L and insulin-like growth factor binding protein 4. In order to ascertain why CLL cells grow poorly in culture, a GEP of 4 CLL patients cells at 0 hr and 24 hr in culture demonstrated over expression of CXCL5, CCL2 and CXCL3, that may recruit immune cells for survival. Treatment with thalidomide, an immunomodulatory agent, showed elevation of CCL5 by GEP but was not cytotoxic to CLL cells. Our data suggest an interplay of several oncogenic pathways, cytokines and immune cells that promote a survival program in CLL.

  • Received September 24, 2008.
  • Revision received November 17, 2008.
  • Accepted April 26, 2009.
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This Article

  1. doi: 10.4061/2009/453634 Hum Genomics Proteomics 453634

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