Detection of FGFR3 by Immunohistochemistry in Multiple Myeloma Is Highly Predictive of t(4;14) by FISH and Is Associated with CD56 (NCAM1) Expression.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5073-5073
Author(s):  
Nizar J. Bahlis ◽  
Birgitte Roland ◽  
Toni Maggliocco ◽  
Ivona Auer ◽  
Douglas A. Stewart ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cyclin D1 ◽  
Cell Adhesion Molecule ◽  
Growth Factor Receptor ◽  
Direct Interaction ◽  
Aberrant Expression ◽  
Downstream Signaling ◽  
Neural Cell Adhesion ◽  
Cd56 Expression ◽  
Adhesive Interactions

Abstract Recent studies have demonstrated that neural cell adhesion molecule CD56 (NCAM1) is involved in multiple adhesive interactions with several different classes of ligands on the cell surface and in the extracellular matrix. One of these ligands is fibroblast growth factor receptor (FGFR) family. While a direct interaction between CD56 (NCAM1) and FGFR3 is yet to be reported we have speculated that such interaction might exist in myeloma cells with aberrant FGFR3 expression. In order to test this hypothesis we have retrospectively examined the presence of t(4;14) in 127 multiple myeloma samples and its correlation with the presence of deletion 13 by FISH; FGFR3 and cyclin D1 expression by immunohistochemistry and CD56 expression as determined by flow cytometry. FISH detected t(4;14) in 32 (25.1%) of 127 MM patient specimens. 71.4% of t(4;14) positive samples were found to have deletion of chromosome 13, in contrast to only 34% in t(4;14) negative samples. Aberrant expression of FGFR3 was detected by immunohistochemistry in 14/21 or 66.7% of t(4;14) positive samples. No expression of FGFR3 was detected in 10 t(4;14) negative samples. As expected low Cyclin D1 expression by IHC was detected in t(4;14) positive samples (5/21 or 23.8%). More importantly all samples positive for FGFR3 by IHC were CD56 positive (14/14 or 100%) and in 21/22 (95.5%) of t(4;14) positive in contrast to 62% in t(4;14) samples. Further work is currently being conducted in order to examine the downstream signaling pathways that might be activated as a result of such possible interaction.

scholarly journals Targeting the Calmodulin-Regulated ErbB/Grb7 Signaling Axis in Cancer Therapy

2013 ◽  
Vol 16 (2) ◽  
pp. 177 ◽  
Author(s):  
Antonio Villalobo ◽  
Irene García-Palmero ◽  
Silviya R. Stateva ◽  
Karim Jellali
Keyword(s):  
Cancer Therapy ◽  
Growth Factor Receptor ◽  
Adaptor Protein ◽  
Short Review ◽  
Receptor Protein ◽  
Pharmacological Intervention ◽  
Erbb Receptors ◽  
Aberrant Expression ◽  
Signaling Mechanism ◽  
Downstream Signaling

Signal transduction pathways essential for the survival and viability of the cell and that frequently present aberrant expression or function in tumors are attractive targets for pharmacological intervention in human cancers. In this short review we will describe the regulation exerted by the calcium-receptor protein calmodulin (CaM) on signaling routes involving the family of ErbB receptors - highlighting the epidermal growth factor receptor (EGFR/ErbB1) and ErbB2 - and the adaptor protein Grb7, a downstream signaling component of these receptors. The signaling mechanism of the ErbB/Grb7 axis and the regulation exerted by CaM on this pathway will be described. We will present a brief overview of the current efforts to inhibit the hyperactivity of ErbB receptors and Grb7 in tumors. The currently available information on targeting the CaM-binding site of these signaling proteins will be analyzed, and the pros and cons of directly targeting CaM versus the CaM-binding domain of the ErbB receptors and Grb7 as potential anti-cancer therapy will be discussed. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Expression of the Neural Cell Adhesion Molecule CD56 Is Associated With Short Remission Duration and Survival in Acute Myeloid Leukemia With t(8; 21)(q22; q22)

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1643-1648 ◽  
Author(s):  
Maria R. Baer ◽  
Carleton C. Stewart ◽  
David Lawrence ◽  
Diane C. Arthur ◽  
John C. Byrd ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Treatment Outcome ◽  
Cell Adhesion ◽  
Myeloid Leukemia ◽  
Cell Adhesion Molecule ◽  
Neural Cell Adhesion Molecule ◽  
Neural Cell Adhesion ◽  
Cd56 Expression ◽  
Acute Myeloid

Abstract Although acute myeloid leukemia (AML) with t(8; 21) (q22; q22) is associated with a high complete remission (CR) rate and prolonged disease-free survival, treatment outcome is not universally favorable. Identifying factors that predict for treatment outcome might allow therapy to be optimized based on risk. AML with t(8; 21) has a distinctive immunophenotype, characterized by expression of the myeloid and stem cell antigens CD13, CD15, CD34, and HLADr, and frequent expression of the B-cell antigen CD19 and the neural cell adhesion molecule CD56, a natural killer cell/stem cell antigen. Because CD56 expression has been associated with both extramedullary leukemia and multidrug resistance, we sought to correlate CD56 expression with treatment outcome in AML with t(8; 21). Pretreatment leukemia cells from 29 adult de novo AML patients with t(8; 21) treated on Cancer and Leukemia Group B (CALGB) protocols were immunophenotyped by multiparameter flow cytometry as part of a prospective immunophenotyping study of adult AML (CALGB 8361). CD56 was expressed in 16 cases (55%). There was no correlation between CD56 expression and age, sex, white blood cell count, granulocyte count, the presence of additional cytogenetic abnormalities, or the presence of extramedullary disease at diagnosis. The CR rate to standard-dose cytarabine and daunorubicin was similar for cases with and without CD56 expression (88% v 92%; P = 1.0). Post-CR therapy included at least one course of high-dose cytarabine in 24 of 26 patients who achieved CR; numbers of courses administered were similar in cases with and without CD56 expression. Although post-CR therapy did not differ, CR duration was significantly shorter in cases with CD56 expression compared with those without (median, 8.7 months v not reached; P = .01), as was survival (median, 16.5 months v not reached; P = .008). We conclude that CD56 expression in AML with t(8; 21) is associated with significantly shorter CR duration and survival. Our results suggest that CD56 expression may be useful in stratifying therapy for this subtype of AML.

The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells

Blood ◽  
2006 ◽  
Vol 107 (10) ◽  
pp. 4039-4046 ◽  
Author(s):  
Suzanne Trudel ◽  
A. Keith Stewart ◽  
Eran Rom ◽  
Ellen Wei ◽  
Zhi Hua Li ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Xenograft Model ◽  
Growth Factor Receptor ◽  
Specific Inhibitor ◽  
Annexin V ◽  
Neutralizing Antibody ◽  
Myeloma Cell ◽  
Downstream Signaling ◽  
Mouse Xenograft Model ◽  
Human Myeloma Cell Line

The association of fibroblast growth factor receptor 3 (FGFR3) expression with t(4;14) multiple myeloma (MM) and the demonstration of the transforming potential of this receptor tyrosine kinase (RTK) make it a particularly attractive target for drug development. We report here a novel and highly specific anti-FGFR3–neutralizing antibody (PRO-001). PRO-001 binds to FGFR3 expressed on transformed cells and inhibits FGFR3 autophosphorylation and downstream signaling. The antibody inhibited the growth of FGFR3-expressing FDCP cells (IC50 of 0.5 μg/mL) but not that of cells expressing FGFR1 or FGFR2, and potently inhibited FGFR3-dependent solid tumor growth in a mouse xenograft model. Furthermore, PRO-001 inhibited the growth of the FGFR3-expressing, human myeloma cell line, UTMC2. Inhibition of viability was still observed when cells were cocultured with stroma or in the presence of IL-6 or IGF-1. PRO-001 did not inhibit constitutive activation of K650E, G384D, and Y373C FGFR3 in myeloma cell lines and failed to inhibit the growth of these cells. Most importantly, however, PRO-001 induced cytotoxic responses in primary t(4;14)+ MM samples with an increase in apoptotic index of 20% to 80% as determined by annexin V staining. The data demonstrate that PRO-001 is a potent and specific inhibitor of FGFR3 and deserves further study for the treatment of FGFR3-expressing myeloma.

Immunohistochemistry accurately predicts FGFR3 aberrant expression and t(4;14) in multiple myeloma

Blood ◽  
2005 ◽  
Vol 106 (1) ◽  
pp. 353-355 ◽  
Author(s):  
Hong Chang ◽  
A. Keith Stewart ◽  
Xiao Ying Qi ◽  
Zhi Hua Li ◽  
Qi Long Yi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Fibroblast Growth Factor Receptor ◽  
Immunoglobulin A ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Strongly Correlated ◽  
Aberrant Expression ◽  
Bone Marrow Biopsies ◽  
Free Survival

The t(4;14) translocation detected by fluorescence in situ hybridization (FISH) is an independent prognostic factor for an adverse outcome of multiple myeloma (MM). Because t(4;14) uniquely results in fibroblast growth factor receptor 3 (FGFR3) expression, decalcified, paraffin-embedded bone marrow biopsies were immunostained for FGFR3, and its expression was correlated with the t(4;14) status. FISH detected t(4;14) in 16 (19%) of 85 MM patient specimens, and immunocytochemistry detected aberrant FGFR3 expression in 13 (15%). Twelve (75%) t(4;14)-positive cases expressed FGFR3, and 12 (92%) FGFR3-positive cases harbored a t(4;14). FGFR3 expression and t(4;14) were strongly correlated (P < .001). FGFR3 expression by immunohistochemistry was associated with the immunoglobulin A (IgA) isotype (P < .001), a shorter progression-free survival (median, 11.5 versus 25.8 months; P < .001), and a shorter overall survival (median, 19.2 versus 46.3 months; P < .001).

scholarly journals Expression of the Neural Cell Adhesion Molecule CD56 Is Associated With Short Remission Duration and Survival in Acute Myeloid Leukemia With t(8; 21)(q22; q22)

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1643-1648 ◽  
Author(s):  
Maria R. Baer ◽  
Carleton C. Stewart ◽  
David Lawrence ◽  
Diane C. Arthur ◽  
John C. Byrd ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Treatment Outcome ◽  
Cell Adhesion ◽  
Myeloid Leukemia ◽  
Cell Adhesion Molecule ◽  
Neural Cell Adhesion Molecule ◽  
Neural Cell Adhesion ◽  
Cd56 Expression ◽  
Acute Myeloid

Although acute myeloid leukemia (AML) with t(8; 21) (q22; q22) is associated with a high complete remission (CR) rate and prolonged disease-free survival, treatment outcome is not universally favorable. Identifying factors that predict for treatment outcome might allow therapy to be optimized based on risk. AML with t(8; 21) has a distinctive immunophenotype, characterized by expression of the myeloid and stem cell antigens CD13, CD15, CD34, and HLADr, and frequent expression of the B-cell antigen CD19 and the neural cell adhesion molecule CD56, a natural killer cell/stem cell antigen. Because CD56 expression has been associated with both extramedullary leukemia and multidrug resistance, we sought to correlate CD56 expression with treatment outcome in AML with t(8; 21). Pretreatment leukemia cells from 29 adult de novo AML patients with t(8; 21) treated on Cancer and Leukemia Group B (CALGB) protocols were immunophenotyped by multiparameter flow cytometry as part of a prospective immunophenotyping study of adult AML (CALGB 8361). CD56 was expressed in 16 cases (55%). There was no correlation between CD56 expression and age, sex, white blood cell count, granulocyte count, the presence of additional cytogenetic abnormalities, or the presence of extramedullary disease at diagnosis. The CR rate to standard-dose cytarabine and daunorubicin was similar for cases with and without CD56 expression (88% v 92%; P = 1.0). Post-CR therapy included at least one course of high-dose cytarabine in 24 of 26 patients who achieved CR; numbers of courses administered were similar in cases with and without CD56 expression. Although post-CR therapy did not differ, CR duration was significantly shorter in cases with CD56 expression compared with those without (median, 8.7 months v not reached; P = .01), as was survival (median, 16.5 months v not reached; P = .008). We conclude that CD56 expression in AML with t(8; 21) is associated with significantly shorter CR duration and survival. Our results suggest that CD56 expression may be useful in stratifying therapy for this subtype of AML.

scholarly journals ADAM-9 (MDC-9/meltrin-γ), a member of the adisintegrin and metalloproteinase family, regulates myeloma-cell–induced interleukin-6 production in osteoblasts by direct interaction with the αvβ5 integrin

Blood ◽  
2006 ◽  
Vol 107 (8) ◽  
pp. 3271-3278 ◽  
Author(s):  
Abdullah Karadag ◽  
Min Zhou ◽  
Peter I. Croucher
Keyword(s):  
Multiple Myeloma ◽  
Signaling Pathways ◽  
Direct Interaction ◽  
Fold Increase ◽  
Myeloma Cell ◽  
Time Dependent ◽  
Myeloma Cells ◽  
Human Osteoblasts ◽  
Growth And Survival ◽  
Downstream Signaling

Abstract ADAM-9, a member of the adisintegrin and metalloproteinase family, contains both metalloproteinase and disintegrin domains. Myeloma cell lines express ADAM-9; however, its function and role in the pathophysiology of multiple myeloma is unknown. The aim of this study was to establish whether primary myeloma cells express ADAM-9, whether ADAM-9 regulates IL-6 production in human osteoblasts (hOBs), whether ADAM-9 interacts with specific integrin heterodimers, and the identity of downstream signaling pathways. Primary myeloma cells demonstrated increased expression of ADAM-9 (P < .01). ADAM-9 promoted a 5-fold increase in IL-6, but not IL-1β mRNA, and a dose- and time-dependent increase in IL-6 production by hOBs (P < .01). IL-6 induction was inhibited by an antibody to the αvβ5 integrin (P < .01) but not by antibodies to other integrin heterodimers. ADAM-9 was shown to bind directly to the αvβ5 integrin on hOBs. Antibodies to ADAM-9 and αvβ5 integrin inhibited myeloma cell–induced IL-6 production by hOBs (P < .01). Furthermore, inhibitors of p38 MAPK and cPLA2, but not NF-κB and JAK2, signaling pathways inhibited ADAM-9–induced IL-6 production by hOBs (P < .01). These data demonstrate that ADAM-9, expressed by myeloma cells, stimulates IL-6 production in hOBs by binding the αvβ5 integrin. This may have important consequences for the growth and survival of myeloma cells in bone.

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