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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.

Mahadevan D, Choi J, Cooke L, Simons B, Riley C, Klinkhammer T, Sud R, Maddipoti S, Hehn S, Garewal H, Spier C - Hum Genomics Proteomics (2009)

Bottom Line: Serum cytokine profiling of 26 low stage patients showed elevation of IFNγ, CSF3, Flt-3L and insulin-like growth factor binding protein 4.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology/Oncology, Arizona Cancer Center, 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 factorβ, 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.

No MeSH data available.


Related in: MedlinePlus

Quantitative real time RT-PCR on 21 low stage CLL patients for selected genes of the WNT/PCP non-canonical pathway where key members are over-expressed.
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fig2: Quantitative real time RT-PCR on 21 low stage CLL patients for selected genes of the WNT/PCP non-canonical pathway where key members are over-expressed.

Mentions: The expression and activation of the classical WNT/FZD signaling cascade has been implicated in CLL. Lu et al., 2004 [19], quantified the GEP of the WNT family and their cognate FZD receptors in CLL cells, and determined the role of WNT signaling in promoting CLL cell survival. Our GEP identified ROR-1 RTK to be over-expressed, which is a member of the non-canonical WNT/PCP pathway. The coreceptor of ROR-1, FZD3 and FZD6 are also over-expressed implicating the activation of the WNT non-canonical pathway in CLL (Table 3(b)). Hence, we analyzed 20 representative members of the canonical and non-canonical pathway from the cell membrane to the nucleus by quantitative real time RT-PCR to ascertain which pathway was active in CLL. The members of the canonical pathway are down regulated (DVL1, AXIN, GSK-3β, TCF-1) except for LEF-1 (Figure 1), while members of the non-canonical pathway are over-expressed (ROR-1, FZD3, JAK2, JNK2, ITK) (Figure 2). GEP identified over-expression of several members of the non-canonical pathway: WNT3 (8-fold), WNT16 (2-fold), FZD3 (3-fold), FZD6 (2-fold) and PCKε (7-fold) to be over-expressed. Western blotting analyses performed on 4 representative CLL patient cells for Ror-1 confirmed expression at the protein level (Supplementary Figure 2). These studies provide evidence for importance of the WNT-ROR-1 non-canonical pathway in CLL.


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.

Mahadevan D, Choi J, Cooke L, Simons B, Riley C, Klinkhammer T, Sud R, Maddipoti S, Hehn S, Garewal H, Spier C - Hum Genomics Proteomics (2009)

Quantitative real time RT-PCR on 21 low stage CLL patients for selected genes of the WNT/PCP non-canonical pathway where key members are over-expressed.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2958625&req=5

fig2: Quantitative real time RT-PCR on 21 low stage CLL patients for selected genes of the WNT/PCP non-canonical pathway where key members are over-expressed.
Mentions: The expression and activation of the classical WNT/FZD signaling cascade has been implicated in CLL. Lu et al., 2004 [19], quantified the GEP of the WNT family and their cognate FZD receptors in CLL cells, and determined the role of WNT signaling in promoting CLL cell survival. Our GEP identified ROR-1 RTK to be over-expressed, which is a member of the non-canonical WNT/PCP pathway. The coreceptor of ROR-1, FZD3 and FZD6 are also over-expressed implicating the activation of the WNT non-canonical pathway in CLL (Table 3(b)). Hence, we analyzed 20 representative members of the canonical and non-canonical pathway from the cell membrane to the nucleus by quantitative real time RT-PCR to ascertain which pathway was active in CLL. The members of the canonical pathway are down regulated (DVL1, AXIN, GSK-3β, TCF-1) except for LEF-1 (Figure 1), while members of the non-canonical pathway are over-expressed (ROR-1, FZD3, JAK2, JNK2, ITK) (Figure 2). GEP identified over-expression of several members of the non-canonical pathway: WNT3 (8-fold), WNT16 (2-fold), FZD3 (3-fold), FZD6 (2-fold) and PCKε (7-fold) to be over-expressed. Western blotting analyses performed on 4 representative CLL patient cells for Ror-1 confirmed expression at the protein level (Supplementary Figure 2). These studies provide evidence for importance of the WNT-ROR-1 non-canonical pathway in CLL.

Bottom Line: Serum cytokine profiling of 26 low stage patients showed elevation of IFNγ, CSF3, Flt-3L and insulin-like growth factor binding protein 4.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology/Oncology, Arizona Cancer Center, 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 factorβ, 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.

No MeSH data available.


Related in: MedlinePlus