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Katherine Tarlock - One of the best experts on this subject based on the ideXlab platform.
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disease characteristics and prognostic implications of cell surface flt3 receptor CD135 expression in pediatric acute myeloid leukemia a report from the children s oncology group
Clinical Cancer Research, 2017Co-Authors: Katherine Tarlock, Todd A Alonzo, Michael R Loken, Robert B Gerbing, Richard Aplenc, Lillian Sung, Susana C Raimondi, Rhonda E. Ries, Betsy A HirschAbstract:Purpose:The FLT3 cell-surface receptor tyrosine kinase (CD135) is expressed in a majority of both acute lymphoid leukemia (ALL) and myeloid leukemia (AML). However, the prognostic significance of CD135 expression in AML remains unclear. We therefore evaluated the association between FLT3 surface expression and disease characteristics and outcomes in pediatric patients with AML. Experimental Design:We analyzed FLT3 receptor expression on AML blasts by multi-dimensional flow cytometry and its association with disease characteristics, clinical outcomes, and FLT3 transcript level in 367 children with AML treated on the Children9s Oncology Group trial AAML0531. Results:There was high variability in blast CD135 cell-surface expression across specimens. CD135 expression measure by flow cytometry was not correlated with FLT3 transcript expression determined by quantitative RT-PCR. Overall, CD135 expression was not significantly different for patients with FLT3/WT and those with FLT3/ITD and FLT3/ALM (p=0.25). High cell-surface CD135 expression was associated with FAB M5 subtype (p<0.001), KMT2A rearrangements (p=0.009) and inversely associated with inv(16)/t(16;16) (p< 0.001). Complete remission rate, overall survival, disease-free survival, and relapse rates were not significantly different between patients with low and high CD135 expression. Conclusions:FLT3 cell-surface expression did not vary by FLT3 mutational status, but high FLT3 expression was strongly associated with KMT2A rearrangements. Our study found that there was no prognostic significance of FLT3 expression in pediatric AML.
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Disease characteristics and prognostic implications of cell-surface FLT3 receptor (CD135) expression in pediatric acute myeloid leukemia: A report from the Children's Oncology Group
Clinical cancer research : an official journal of the American Association for Cancer Research, 2017Co-Authors: Katherine Tarlock, Todd A Alonzo, Michael R Loken, Robert B Gerbing, Richard Aplenc, Lillian Sung, Susana C Raimondi, Betsy A Hirsch, Rhonda E. Ries, Samir B KahwashAbstract:Purpose:The FLT3 cell-surface receptor tyrosine kinase (CD135) is expressed in a majority of both acute lymphoid leukemia (ALL) and myeloid leukemia (AML). However, the prognostic significance of CD135 expression in AML remains unclear. We therefore evaluated the association between FLT3 surface expression and disease characteristics and outcomes in pediatric patients with AML. Experimental Design:We analyzed FLT3 receptor expression on AML blasts by multi-dimensional flow cytometry and its association with disease characteristics, clinical outcomes, and FLT3 transcript level in 367 children with AML treated on the Children9s Oncology Group trial AAML0531. Results:There was high variability in blast CD135 cell-surface expression across specimens. CD135 expression measure by flow cytometry was not correlated with FLT3 transcript expression determined by quantitative RT-PCR. Overall, CD135 expression was not significantly different for patients with FLT3/WT and those with FLT3/ITD and FLT3/ALM (p=0.25). High cell-surface CD135 expression was associated with FAB M5 subtype (p
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disease characteristics and prognostic implications of cell surface flt3 receptor CD135 expression in pediatric acute myeloid leukemia a report from children s oncology group
Blood, 2013Co-Authors: Katherine Tarlock, Todd A Alonzo, Michael R Loken, Robert B Gerbing, Richard Aplenc, Lillian Sung, Susana C Raimondi, Betsy A Hirsch, Samir B Kahwash, Amy HeeremamckenneyAbstract:FLT3 is a highly expressed cell surface receptor in a majority of acute leukemias with near universal expression in acute myeloid leukemia (AML). High FLT3 expression level in conjunction with 11q23/ MLL -rearrangement has been associated with poor prognosis in pre-B acute lymphoblastic leukemia (ALL) and is considered a potential therapeutic target through FLT3 inhibition. In vitro studies have demonstrated enhanced sensitivity of ALL and AML cells with high FLT3 expression to the cytotoxic effects of FLT3 inhibition. Although the clinical impact of high allelic ratio FLT3 / ITD has been demonstrated in AML, the significance of FLT3 expression in those without the mutation has not been well studied, and all previous studies have been limited to evaluation of FLT3 transcript levels for correlation with outcome. Here we present the results of a prospective evaluation of FLT3 cell surface protein expression (CD135) on the diagnostic leukemic blast population as determined by multi-dimensional flow cytometry (MDF) in specimens from patients treated on COG AAML0531. Of the 495 patients enrolled after September 25, 2008, 366 patients enrolled on the accompanying biology study and had diagnostic specimens for evaluation of central CD135 expression by MDF. All diagnostic specimens underwent central MDF analysis for CD135 expression. FLT3 mutation data was available on all 366 patients, 57 patients were FLT3 /ITD (15.6%), 21 were FLT3 /ALM (5.7%) and the remaining 290 were FLT3 wild type (FLT3/WT). There was significant variability of CD135 expression across the population with a mean fluorescence intensity (MFI) ranging from 3-232 (median 18). Median CD135 expression for those with FLT3 /ITD, FLT3 /ALM, FLT3 /WT was 22 vs. 19 vs. 17 respectively (p=NS). Patients were divided into quartiles based on CD135 expression and clinical characteristics and outcome were correlated with CD135 expression across the four quartiles. There was not a significant difference in CD135 expression by age, gender, race, or ethnicity across the four quartiles. Those with high CD135 expression (Q4) had similar median diagnostic WBC counts as those with lower CD135 (Q1-3), although median diagnostic blast % in those in Q4 was significantly elevated (p=0.003). Nearly half of those in Q4 were FAB M5 compared to 13% in Q1-3 (p<0.001) and all those with FAB M7 had low CD135 expression (p=0.004). Evaluation of the diagnostic cytogenetics and CD135 expression demonstrated significant correlation of CD135 expression with MLL translocations, as 22% of patients in Q4 had MLL translocations vs. 11% in Q1-3 (p=0.005). This was primarily driven by patients with t(9;11), p=0.001. There was an inverse correlation between inv(16) and CD135 expression as only 2% of those in Q4 had inv(16) compared to 15% in Q1-3 (p<0.001). CD135 was then correlated with response to induction and post-induction outcome. Complete remission (CR) rate was comparable between those with high or lower CD135 expression (p=0.76). Those with high or lower CD135 expression had similar 3-yr overall survival (OS) from diagnosis of 70% and 66% respectively (p=0.9) and relapse risk from CR of 42% and 36% respectively (p=0.35). Given the known prognostic and therapeutic significance of FLT3 /ITD, we evaluated any prognostic implications of FLT3 expression in patients without FLT3 /ITD, most of whom lack other cytogenetic risk features. Similar to the entire cohort, in the FLT3 /ITD-negative cohort CD135 expression correlated with FAB M5 (p<0.001), t(9;11), (p<0.001) and inversely correlated with inv(16), p=0.001. 3-yr OS for those in Q4 was 71% vs. 67% in Q1-3 (p=0.955). Given the association of MLL and CD135 expression, we evaluated the association of CD135 expression with outcome in patients with MLL translocations (N=73); in these patients the 3-yr event free survival (EFS) was similar between those with high or lower CD135 expression (p=0.621). In summary, we found that CD135 surface expression did not correlate with FLT3 mutations or clinical outcomes. Although FLT3 expression in FLT3 /ITD-negative patients does not appear to offer additional prognostic information with current therapy, it may provide a therapeutic target in a subset of high expressing patients. This study also demonstrates that elevated FLT3 expression is associated with MLL rearrangements and warrants further study in this population with regards to potential prognostic and therapeutic implications. Disclosures: No relevant conflicts of interest to declare.
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Disease Characteristics and Prognostic Implications Of Cell Surface FLT3 Receptor (CD135) Expression In Pediatric Acute Myeloid Leukemia – A Report From Children’s Oncology Group
Blood, 2013Co-Authors: Katherine Tarlock, Todd A Alonzo, Michael R Loken, Robert B Gerbing, Richard Aplenc, Lillian Sung, Susana C Raimondi, Betsy A Hirsch, Samir B Kahwash, Amy Heerema-mckenneyAbstract:FLT3 is a highly expressed cell surface receptor in a majority of acute leukemias with near universal expression in acute myeloid leukemia (AML). High FLT3 expression level in conjunction with 11q23/ MLL -rearrangement has been associated with poor prognosis in pre-B acute lymphoblastic leukemia (ALL) and is considered a potential therapeutic target through FLT3 inhibition. In vitro studies have demonstrated enhanced sensitivity of ALL and AML cells with high FLT3 expression to the cytotoxic effects of FLT3 inhibition. Although the clinical impact of high allelic ratio FLT3 / ITD has been demonstrated in AML, the significance of FLT3 expression in those without the mutation has not been well studied, and all previous studies have been limited to evaluation of FLT3 transcript levels for correlation with outcome. Here we present the results of a prospective evaluation of FLT3 cell surface protein expression (CD135) on the diagnostic leukemic blast population as determined by multi-dimensional flow cytometry (MDF) in specimens from patients treated on COG AAML0531. Of the 495 patients enrolled after September 25, 2008, 366 patients enrolled on the accompanying biology study and had diagnostic specimens for evaluation of central CD135 expression by MDF. All diagnostic specimens underwent central MDF analysis for CD135 expression. FLT3 mutation data was available on all 366 patients, 57 patients were FLT3 /ITD (15.6%), 21 were FLT3 /ALM (5.7%) and the remaining 290 were FLT3 wild type (FLT3/WT). There was significant variability of CD135 expression across the population with a mean fluorescence intensity (MFI) ranging from 3-232 (median 18). Median CD135 expression for those with FLT3 /ITD, FLT3 /ALM, FLT3 /WT was 22 vs. 19 vs. 17 respectively (p=NS). Patients were divided into quartiles based on CD135 expression and clinical characteristics and outcome were correlated with CD135 expression across the four quartiles. There was not a significant difference in CD135 expression by age, gender, race, or ethnicity across the four quartiles. Those with high CD135 expression (Q4) had similar median diagnostic WBC counts as those with lower CD135 (Q1-3), although median diagnostic blast % in those in Q4 was significantly elevated (p=0.003). Nearly half of those in Q4 were FAB M5 compared to 13% in Q1-3 (p
Saida Aarrass - One of the best experts on this subject based on the ideXlab platform.
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FMS-related tyrosine kinase 3 ligand (Flt3L)/CD135 axis in rheumatoid arthritis
Arthritis research & therapy, 2013Co-Authors: M I Ramos, Samuel Garcia Perez, Saida Aarrass, Boy Helder, Pleun Broekstra, Daan M Gerlag, Kris A. Reedquist, Paul P. Tak, M C LebreAbstract:The FMS-related tyrosine kinase 3 ligand (Flt3L)/CD135 axis plays a fundamental role in proliferation and differentiation of dendritic cells (DCs). As DCs play an important role in rheumatoid arthritis (RA) immunopathology we studied in detail the Flt3L/CD135 axis in RA patients. The levels of Flt3L in (paired) serum and synovial fluid (SF) were quantified by enzyme-link immunosorbent assay (ELISA). Expression of Flt3L and CD135 in paired peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) was quantified by fluorescence-activated cell sorting (FACS). The expression of Flt3L, CD135 and TNF-Converting Enzyme (TACE) in synovial tissues (STs) and in vitro polarized macrophages and monocyte-derived DCs (Mo-DCs) was assessed by quantitative PCR (qPCR). CD135 ST expression was evaluated by immunohistochemistry and TACE ST expression was assessed by immunofluorescence. Flt3L serum levels were assessed in RA patients treated with oral prednisolone or adalimumab. Flt3L levels in RA serum, SF and ST were significantly elevated compared to gout patients and healthy individuals (HI). RA SF monocytes, natural killer cells and DCs expressed high levels of Flt3L and CD135 compared to HI. RA ST CD68+ and CD163+ macrophages, CD55+ fibroblast-like synoviocytes (FLS), CD31+ endothelial cells or infiltrating monocytes and CD19+ B cells co-expressed TACE. IFN-γ-differentiated macrophages expressed higher levels of Flt3L compared to other polarized macrophages. Importantly, Flt3L serum levels were reduced by effective therapy. The Flt3L/CD135 axis is active in RA patients and is responsive to both prednisolone and adalimumab treatment. Conceivably, this ligand receptor pair represents a novel therapeutic target.
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fms like tyrosine kinase 3 ligand CD135 in arthritis a new inflammatory system in ra
Annals of the Rheumatic Diseases, 2011Co-Authors: In M S Ramos, Saida Aarrass, Paul P. Tak, Lisa G. M. Van Baarsen, Cristina M LebreAbstract:Background Fms-like tyrosine kinase 3 ligand (Flt3L) is a potent endogenous growth factor for myeloid dendritic cells (mDC) and plasmacytoid dendritic cells (pDC). Its administration to mice and humans leads to dramatic increases of various DC subsets while Flt3L−/− mice show reduced DC numbers. Flt3L and its receptor (CD135) have been poorly studied in the setting of autoimmune diseases in general. Typically, CD135 is expressed on early myeloid and lymphoid progenitors and is activated by its soluble ligand, Flt3L. The highly differentiated cellular pattern in rheumatoid arthritis (RA) synovium made the authors hypothesise that Flt3L, with its ability to induce proliferation and differentiation, could be of importance in induction and/or progression of arthritis. Material and methods Patients with active RA, psoriatic arthritis (PsA), spondyloarthritis (SpA), osteoarthritis (OA), gout and healthy donors (HD) were included in this study. Soluble (s)Flt3L levels in synovial fluid (SF) and serum were determined by ELISA. Expression of membrane-bound (m)Flt3L and Flt3L receptor (CD135) in peripheral blood mononuclear cells (PBMC) and SFMC were assessed by FACS. In addition, immunohistochemical analysis of Flt3L and CD135 was performed in RA, PsA, gout, OA and HD synovial tissues. Results SF levels of Flt3L in RA (n=103), PsA (n=33), and SpA (n=32), OA (n=8) and gout (n=43) were significantly higher compared to paired serum. In addition, Flt3L levels were significantly higher in RA, PsA and SpA SFs compared to gout SF. In peripheral blood (PB) monocytes, B cells and mDC the expression of mFlt3L in RA was higher compared to HD. Flt3L receptor expression was confined to monocytes and mDC and higher in RA SF compared to PB. Immunohistochemistry and immunofluorescence data showed the presence of Flt3L and CD135 in RA ST. Interestingly, microarray data of RA synovial tissue showed that CD135 expression is increased in patients with high inflammatory gene profile compared to low inflammatory gene profile. There is no different in Flt3L expression between RA and OA confirming the ELISA data. In addition, anti-TNF therapy reduced Flt3L serum levels in RA patients. Conclusion The data presented in this study point to inflammatory role for Flt3L/CD135 system. Moreover, as the Flt3L/CD135 system is implicated in the generation of DC and B cells, inflammatory cells important in RA pathogenesis, this system might be of importance in RA. Achieving a detailed understanding of Flt3L function(s) in arthritis may lead to the development of novel immunotherapies for RA and other immune-mediated inflammatory diseases.
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Fms-like tyrosine kinase 3 ligand/CD135 in arthritis: a new inflammatory system in RA?
Annals of the Rheumatic Diseases, 2011Co-Authors: M In≖s Ramos, Saida Aarrass, Paul P. Tak, Lisa G. M. Van Baarsen, M Cristina LebreAbstract:Background Fms-like tyrosine kinase 3 ligand (Flt3L) is a potent endogenous growth factor for myeloid dendritic cells (mDC) and plasmacytoid dendritic cells (pDC). Its administration to mice and humans leads to dramatic increases of various DC subsets while Flt3L−/− mice show reduced DC numbers. Flt3L and its receptor (CD135) have been poorly studied in the setting of autoimmune diseases in general. Typically, CD135 is expressed on early myeloid and lymphoid progenitors and is activated by its soluble ligand, Flt3L. The highly differentiated cellular pattern in rheumatoid arthritis (RA) synovium made the authors hypothesise that Flt3L, with its ability to induce proliferation and differentiation, could be of importance in induction and/or progression of arthritis. Material and methods Patients with active RA, psoriatic arthritis (PsA), spondyloarthritis (SpA), osteoarthritis (OA), gout and healthy donors (HD) were included in this study. Soluble (s)Flt3L levels in synovial fluid (SF) and serum were determined by ELISA. Expression of membrane-bound (m)Flt3L and Flt3L receptor (CD135) in peripheral blood mononuclear cells (PBMC) and SFMC were assessed by FACS. In addition, immunohistochemical analysis of Flt3L and CD135 was performed in RA, PsA, gout, OA and HD synovial tissues. Results SF levels of Flt3L in RA (n=103), PsA (n=33), and SpA (n=32), OA (n=8) and gout (n=43) were significantly higher compared to paired serum. In addition, Flt3L levels were significantly higher in RA, PsA and SpA SFs compared to gout SF. In peripheral blood (PB) monocytes, B cells and mDC the expression of mFlt3L in RA was higher compared to HD. Flt3L receptor expression was confined to monocytes and mDC and higher in RA SF compared to PB. Immunohistochemistry and immunofluorescence data showed the presence of Flt3L and CD135 in RA ST. Interestingly, microarray data of RA synovial tissue showed that CD135 expression is increased in patients with high inflammatory gene profile compared to low inflammatory gene profile. There is no different in Flt3L expression between RA and OA confirming the ELISA data. In addition, anti-TNF therapy reduced Flt3L serum levels in RA patients. Conclusion The data presented in this study point to inflammatory role for Flt3L/CD135 system. Moreover, as the Flt3L/CD135 system is implicated in the generation of DC and B cells, inflammatory cells important in RA pathogenesis, this system might be of importance in RA. Achieving a detailed understanding of Flt3L function(s) in arthritis may lead to the development of novel immunotherapies for RA and other immune-mediated inflammatory diseases.
Paul P. Tak - One of the best experts on this subject based on the ideXlab platform.
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FMS-related tyrosine kinase 3 ligand (Flt3L)/CD135 axis in rheumatoid arthritis
Arthritis research & therapy, 2013Co-Authors: M I Ramos, Samuel Garcia Perez, Saida Aarrass, Boy Helder, Pleun Broekstra, Daan M Gerlag, Kris A. Reedquist, Paul P. Tak, M C LebreAbstract:The FMS-related tyrosine kinase 3 ligand (Flt3L)/CD135 axis plays a fundamental role in proliferation and differentiation of dendritic cells (DCs). As DCs play an important role in rheumatoid arthritis (RA) immunopathology we studied in detail the Flt3L/CD135 axis in RA patients. The levels of Flt3L in (paired) serum and synovial fluid (SF) were quantified by enzyme-link immunosorbent assay (ELISA). Expression of Flt3L and CD135 in paired peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) was quantified by fluorescence-activated cell sorting (FACS). The expression of Flt3L, CD135 and TNF-Converting Enzyme (TACE) in synovial tissues (STs) and in vitro polarized macrophages and monocyte-derived DCs (Mo-DCs) was assessed by quantitative PCR (qPCR). CD135 ST expression was evaluated by immunohistochemistry and TACE ST expression was assessed by immunofluorescence. Flt3L serum levels were assessed in RA patients treated with oral prednisolone or adalimumab. Flt3L levels in RA serum, SF and ST were significantly elevated compared to gout patients and healthy individuals (HI). RA SF monocytes, natural killer cells and DCs expressed high levels of Flt3L and CD135 compared to HI. RA ST CD68+ and CD163+ macrophages, CD55+ fibroblast-like synoviocytes (FLS), CD31+ endothelial cells or infiltrating monocytes and CD19+ B cells co-expressed TACE. IFN-γ-differentiated macrophages expressed higher levels of Flt3L compared to other polarized macrophages. Importantly, Flt3L serum levels were reduced by effective therapy. The Flt3L/CD135 axis is active in RA patients and is responsive to both prednisolone and adalimumab treatment. Conceivably, this ligand receptor pair represents a novel therapeutic target.
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fms like tyrosine kinase 3 ligand CD135 in arthritis a new inflammatory system in ra
Annals of the Rheumatic Diseases, 2011Co-Authors: In M S Ramos, Saida Aarrass, Paul P. Tak, Lisa G. M. Van Baarsen, Cristina M LebreAbstract:Background Fms-like tyrosine kinase 3 ligand (Flt3L) is a potent endogenous growth factor for myeloid dendritic cells (mDC) and plasmacytoid dendritic cells (pDC). Its administration to mice and humans leads to dramatic increases of various DC subsets while Flt3L−/− mice show reduced DC numbers. Flt3L and its receptor (CD135) have been poorly studied in the setting of autoimmune diseases in general. Typically, CD135 is expressed on early myeloid and lymphoid progenitors and is activated by its soluble ligand, Flt3L. The highly differentiated cellular pattern in rheumatoid arthritis (RA) synovium made the authors hypothesise that Flt3L, with its ability to induce proliferation and differentiation, could be of importance in induction and/or progression of arthritis. Material and methods Patients with active RA, psoriatic arthritis (PsA), spondyloarthritis (SpA), osteoarthritis (OA), gout and healthy donors (HD) were included in this study. Soluble (s)Flt3L levels in synovial fluid (SF) and serum were determined by ELISA. Expression of membrane-bound (m)Flt3L and Flt3L receptor (CD135) in peripheral blood mononuclear cells (PBMC) and SFMC were assessed by FACS. In addition, immunohistochemical analysis of Flt3L and CD135 was performed in RA, PsA, gout, OA and HD synovial tissues. Results SF levels of Flt3L in RA (n=103), PsA (n=33), and SpA (n=32), OA (n=8) and gout (n=43) were significantly higher compared to paired serum. In addition, Flt3L levels were significantly higher in RA, PsA and SpA SFs compared to gout SF. In peripheral blood (PB) monocytes, B cells and mDC the expression of mFlt3L in RA was higher compared to HD. Flt3L receptor expression was confined to monocytes and mDC and higher in RA SF compared to PB. Immunohistochemistry and immunofluorescence data showed the presence of Flt3L and CD135 in RA ST. Interestingly, microarray data of RA synovial tissue showed that CD135 expression is increased in patients with high inflammatory gene profile compared to low inflammatory gene profile. There is no different in Flt3L expression between RA and OA confirming the ELISA data. In addition, anti-TNF therapy reduced Flt3L serum levels in RA patients. Conclusion The data presented in this study point to inflammatory role for Flt3L/CD135 system. Moreover, as the Flt3L/CD135 system is implicated in the generation of DC and B cells, inflammatory cells important in RA pathogenesis, this system might be of importance in RA. Achieving a detailed understanding of Flt3L function(s) in arthritis may lead to the development of novel immunotherapies for RA and other immune-mediated inflammatory diseases.
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Fms-like tyrosine kinase 3 ligand/CD135 in arthritis: a new inflammatory system in RA?
Annals of the Rheumatic Diseases, 2011Co-Authors: M In≖s Ramos, Saida Aarrass, Paul P. Tak, Lisa G. M. Van Baarsen, M Cristina LebreAbstract:Background Fms-like tyrosine kinase 3 ligand (Flt3L) is a potent endogenous growth factor for myeloid dendritic cells (mDC) and plasmacytoid dendritic cells (pDC). Its administration to mice and humans leads to dramatic increases of various DC subsets while Flt3L−/− mice show reduced DC numbers. Flt3L and its receptor (CD135) have been poorly studied in the setting of autoimmune diseases in general. Typically, CD135 is expressed on early myeloid and lymphoid progenitors and is activated by its soluble ligand, Flt3L. The highly differentiated cellular pattern in rheumatoid arthritis (RA) synovium made the authors hypothesise that Flt3L, with its ability to induce proliferation and differentiation, could be of importance in induction and/or progression of arthritis. Material and methods Patients with active RA, psoriatic arthritis (PsA), spondyloarthritis (SpA), osteoarthritis (OA), gout and healthy donors (HD) were included in this study. Soluble (s)Flt3L levels in synovial fluid (SF) and serum were determined by ELISA. Expression of membrane-bound (m)Flt3L and Flt3L receptor (CD135) in peripheral blood mononuclear cells (PBMC) and SFMC were assessed by FACS. In addition, immunohistochemical analysis of Flt3L and CD135 was performed in RA, PsA, gout, OA and HD synovial tissues. Results SF levels of Flt3L in RA (n=103), PsA (n=33), and SpA (n=32), OA (n=8) and gout (n=43) were significantly higher compared to paired serum. In addition, Flt3L levels were significantly higher in RA, PsA and SpA SFs compared to gout SF. In peripheral blood (PB) monocytes, B cells and mDC the expression of mFlt3L in RA was higher compared to HD. Flt3L receptor expression was confined to monocytes and mDC and higher in RA SF compared to PB. Immunohistochemistry and immunofluorescence data showed the presence of Flt3L and CD135 in RA ST. Interestingly, microarray data of RA synovial tissue showed that CD135 expression is increased in patients with high inflammatory gene profile compared to low inflammatory gene profile. There is no different in Flt3L expression between RA and OA confirming the ELISA data. In addition, anti-TNF therapy reduced Flt3L serum levels in RA patients. Conclusion The data presented in this study point to inflammatory role for Flt3L/CD135 system. Moreover, as the Flt3L/CD135 system is implicated in the generation of DC and B cells, inflammatory cells important in RA pathogenesis, this system might be of importance in RA. Achieving a detailed understanding of Flt3L function(s) in arthritis may lead to the development of novel immunotherapies for RA and other immune-mediated inflammatory diseases.
Betsy A Hirsch - One of the best experts on this subject based on the ideXlab platform.
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disease characteristics and prognostic implications of cell surface flt3 receptor CD135 expression in pediatric acute myeloid leukemia a report from the children s oncology group
Clinical Cancer Research, 2017Co-Authors: Katherine Tarlock, Todd A Alonzo, Michael R Loken, Robert B Gerbing, Richard Aplenc, Lillian Sung, Susana C Raimondi, Rhonda E. Ries, Betsy A HirschAbstract:Purpose:The FLT3 cell-surface receptor tyrosine kinase (CD135) is expressed in a majority of both acute lymphoid leukemia (ALL) and myeloid leukemia (AML). However, the prognostic significance of CD135 expression in AML remains unclear. We therefore evaluated the association between FLT3 surface expression and disease characteristics and outcomes in pediatric patients with AML. Experimental Design:We analyzed FLT3 receptor expression on AML blasts by multi-dimensional flow cytometry and its association with disease characteristics, clinical outcomes, and FLT3 transcript level in 367 children with AML treated on the Children9s Oncology Group trial AAML0531. Results:There was high variability in blast CD135 cell-surface expression across specimens. CD135 expression measure by flow cytometry was not correlated with FLT3 transcript expression determined by quantitative RT-PCR. Overall, CD135 expression was not significantly different for patients with FLT3/WT and those with FLT3/ITD and FLT3/ALM (p=0.25). High cell-surface CD135 expression was associated with FAB M5 subtype (p<0.001), KMT2A rearrangements (p=0.009) and inversely associated with inv(16)/t(16;16) (p< 0.001). Complete remission rate, overall survival, disease-free survival, and relapse rates were not significantly different between patients with low and high CD135 expression. Conclusions:FLT3 cell-surface expression did not vary by FLT3 mutational status, but high FLT3 expression was strongly associated with KMT2A rearrangements. Our study found that there was no prognostic significance of FLT3 expression in pediatric AML.
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Disease characteristics and prognostic implications of cell-surface FLT3 receptor (CD135) expression in pediatric acute myeloid leukemia: A report from the Children's Oncology Group
Clinical cancer research : an official journal of the American Association for Cancer Research, 2017Co-Authors: Katherine Tarlock, Todd A Alonzo, Michael R Loken, Robert B Gerbing, Richard Aplenc, Lillian Sung, Susana C Raimondi, Betsy A Hirsch, Rhonda E. Ries, Samir B KahwashAbstract:Purpose:The FLT3 cell-surface receptor tyrosine kinase (CD135) is expressed in a majority of both acute lymphoid leukemia (ALL) and myeloid leukemia (AML). However, the prognostic significance of CD135 expression in AML remains unclear. We therefore evaluated the association between FLT3 surface expression and disease characteristics and outcomes in pediatric patients with AML. Experimental Design:We analyzed FLT3 receptor expression on AML blasts by multi-dimensional flow cytometry and its association with disease characteristics, clinical outcomes, and FLT3 transcript level in 367 children with AML treated on the Children9s Oncology Group trial AAML0531. Results:There was high variability in blast CD135 cell-surface expression across specimens. CD135 expression measure by flow cytometry was not correlated with FLT3 transcript expression determined by quantitative RT-PCR. Overall, CD135 expression was not significantly different for patients with FLT3/WT and those with FLT3/ITD and FLT3/ALM (p=0.25). High cell-surface CD135 expression was associated with FAB M5 subtype (p
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disease characteristics and prognostic implications of cell surface flt3 receptor CD135 expression in pediatric acute myeloid leukemia a report from children s oncology group
Blood, 2013Co-Authors: Katherine Tarlock, Todd A Alonzo, Michael R Loken, Robert B Gerbing, Richard Aplenc, Lillian Sung, Susana C Raimondi, Betsy A Hirsch, Samir B Kahwash, Amy HeeremamckenneyAbstract:FLT3 is a highly expressed cell surface receptor in a majority of acute leukemias with near universal expression in acute myeloid leukemia (AML). High FLT3 expression level in conjunction with 11q23/ MLL -rearrangement has been associated with poor prognosis in pre-B acute lymphoblastic leukemia (ALL) and is considered a potential therapeutic target through FLT3 inhibition. In vitro studies have demonstrated enhanced sensitivity of ALL and AML cells with high FLT3 expression to the cytotoxic effects of FLT3 inhibition. Although the clinical impact of high allelic ratio FLT3 / ITD has been demonstrated in AML, the significance of FLT3 expression in those without the mutation has not been well studied, and all previous studies have been limited to evaluation of FLT3 transcript levels for correlation with outcome. Here we present the results of a prospective evaluation of FLT3 cell surface protein expression (CD135) on the diagnostic leukemic blast population as determined by multi-dimensional flow cytometry (MDF) in specimens from patients treated on COG AAML0531. Of the 495 patients enrolled after September 25, 2008, 366 patients enrolled on the accompanying biology study and had diagnostic specimens for evaluation of central CD135 expression by MDF. All diagnostic specimens underwent central MDF analysis for CD135 expression. FLT3 mutation data was available on all 366 patients, 57 patients were FLT3 /ITD (15.6%), 21 were FLT3 /ALM (5.7%) and the remaining 290 were FLT3 wild type (FLT3/WT). There was significant variability of CD135 expression across the population with a mean fluorescence intensity (MFI) ranging from 3-232 (median 18). Median CD135 expression for those with FLT3 /ITD, FLT3 /ALM, FLT3 /WT was 22 vs. 19 vs. 17 respectively (p=NS). Patients were divided into quartiles based on CD135 expression and clinical characteristics and outcome were correlated with CD135 expression across the four quartiles. There was not a significant difference in CD135 expression by age, gender, race, or ethnicity across the four quartiles. Those with high CD135 expression (Q4) had similar median diagnostic WBC counts as those with lower CD135 (Q1-3), although median diagnostic blast % in those in Q4 was significantly elevated (p=0.003). Nearly half of those in Q4 were FAB M5 compared to 13% in Q1-3 (p<0.001) and all those with FAB M7 had low CD135 expression (p=0.004). Evaluation of the diagnostic cytogenetics and CD135 expression demonstrated significant correlation of CD135 expression with MLL translocations, as 22% of patients in Q4 had MLL translocations vs. 11% in Q1-3 (p=0.005). This was primarily driven by patients with t(9;11), p=0.001. There was an inverse correlation between inv(16) and CD135 expression as only 2% of those in Q4 had inv(16) compared to 15% in Q1-3 (p<0.001). CD135 was then correlated with response to induction and post-induction outcome. Complete remission (CR) rate was comparable between those with high or lower CD135 expression (p=0.76). Those with high or lower CD135 expression had similar 3-yr overall survival (OS) from diagnosis of 70% and 66% respectively (p=0.9) and relapse risk from CR of 42% and 36% respectively (p=0.35). Given the known prognostic and therapeutic significance of FLT3 /ITD, we evaluated any prognostic implications of FLT3 expression in patients without FLT3 /ITD, most of whom lack other cytogenetic risk features. Similar to the entire cohort, in the FLT3 /ITD-negative cohort CD135 expression correlated with FAB M5 (p<0.001), t(9;11), (p<0.001) and inversely correlated with inv(16), p=0.001. 3-yr OS for those in Q4 was 71% vs. 67% in Q1-3 (p=0.955). Given the association of MLL and CD135 expression, we evaluated the association of CD135 expression with outcome in patients with MLL translocations (N=73); in these patients the 3-yr event free survival (EFS) was similar between those with high or lower CD135 expression (p=0.621). In summary, we found that CD135 surface expression did not correlate with FLT3 mutations or clinical outcomes. Although FLT3 expression in FLT3 /ITD-negative patients does not appear to offer additional prognostic information with current therapy, it may provide a therapeutic target in a subset of high expressing patients. This study also demonstrates that elevated FLT3 expression is associated with MLL rearrangements and warrants further study in this population with regards to potential prognostic and therapeutic implications. Disclosures: No relevant conflicts of interest to declare.
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Disease Characteristics and Prognostic Implications Of Cell Surface FLT3 Receptor (CD135) Expression In Pediatric Acute Myeloid Leukemia – A Report From Children’s Oncology Group
Blood, 2013Co-Authors: Katherine Tarlock, Todd A Alonzo, Michael R Loken, Robert B Gerbing, Richard Aplenc, Lillian Sung, Susana C Raimondi, Betsy A Hirsch, Samir B Kahwash, Amy Heerema-mckenneyAbstract:FLT3 is a highly expressed cell surface receptor in a majority of acute leukemias with near universal expression in acute myeloid leukemia (AML). High FLT3 expression level in conjunction with 11q23/ MLL -rearrangement has been associated with poor prognosis in pre-B acute lymphoblastic leukemia (ALL) and is considered a potential therapeutic target through FLT3 inhibition. In vitro studies have demonstrated enhanced sensitivity of ALL and AML cells with high FLT3 expression to the cytotoxic effects of FLT3 inhibition. Although the clinical impact of high allelic ratio FLT3 / ITD has been demonstrated in AML, the significance of FLT3 expression in those without the mutation has not been well studied, and all previous studies have been limited to evaluation of FLT3 transcript levels for correlation with outcome. Here we present the results of a prospective evaluation of FLT3 cell surface protein expression (CD135) on the diagnostic leukemic blast population as determined by multi-dimensional flow cytometry (MDF) in specimens from patients treated on COG AAML0531. Of the 495 patients enrolled after September 25, 2008, 366 patients enrolled on the accompanying biology study and had diagnostic specimens for evaluation of central CD135 expression by MDF. All diagnostic specimens underwent central MDF analysis for CD135 expression. FLT3 mutation data was available on all 366 patients, 57 patients were FLT3 /ITD (15.6%), 21 were FLT3 /ALM (5.7%) and the remaining 290 were FLT3 wild type (FLT3/WT). There was significant variability of CD135 expression across the population with a mean fluorescence intensity (MFI) ranging from 3-232 (median 18). Median CD135 expression for those with FLT3 /ITD, FLT3 /ALM, FLT3 /WT was 22 vs. 19 vs. 17 respectively (p=NS). Patients were divided into quartiles based on CD135 expression and clinical characteristics and outcome were correlated with CD135 expression across the four quartiles. There was not a significant difference in CD135 expression by age, gender, race, or ethnicity across the four quartiles. Those with high CD135 expression (Q4) had similar median diagnostic WBC counts as those with lower CD135 (Q1-3), although median diagnostic blast % in those in Q4 was significantly elevated (p=0.003). Nearly half of those in Q4 were FAB M5 compared to 13% in Q1-3 (p
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Role of CD135/CD117 on Prognosis and Overall Survival of Acute Myeloid Leukemia.
Asian Pacific journal of cancer prevention : APJCP, 2019Co-Authors: Mortaza Raeisi, Ali Reza Nikhanfar, Babak Nejate, Ali Akabr Movassaghpour Akbari, Roya Dolatkhah, Yousef Roosta, Zohreh SanaatAbstract:Background: The key proliferative RTKs for AML include c-KIT receptor (CD117) and FLT-3 receptor (CD135). The aim of this study was to evaluate the CD135 and CD117 expression, co-expression of CD135 and CD117 (CD135+CD117), and the association of that co-expression with Event Free Survival (DFS) and Overall Survival (OS) rates. Material and Methods: We analyzed CD117 and CD135 expression on AML blasts by flow cytometry and its association with Event Free Survival (DFS) and Overall Survival (OS) in 66 AML treated on Hematology-Oncology Research Center, Iran, Tabriz. Results: The overall OS and EFS were 50% and 80.3% respectively during our study. Cox-regression analysis revealed that a poor EFS was significantly associated a low CD135 (HR 0.34, 95% CI 0.13–0.88, P = 0.02). Conclusion: This is the first study from Iran to show that the expressions of CD135, CD117 is easily measurable by routine diagnostic flow-cytometry, and CD135+117 were not significantly associated with CR, EFS, or OS .
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role of CD135 cd117 on prognosis and overall survival of acute myeloid leukemia
Asian Pacific Journal of Cancer Prevention, 2019Co-Authors: Mortaza Raeisi, Ali Reza Nikhanfar, Babak Nejate, Ali Akabr Movassaghpour Akbari, Roya Dolatkhah, Yousef Roosta, Zohreh SanaatAbstract:Background: The key proliferative RTKs for AML include c-KIT receptor (CD117) and FLT-3 receptor (CD135). The aim of this study was to evaluate the CD135 and CD117 expression, co-expression of CD135 and CD117 (CD135+CD117), and the association of that co-expression with Event Free Survival (DFS) and Overall Survival (OS) rates. Material and Methods: We analyzed CD117 and CD135 expression on AML blasts by flow cytometry and its association with Event Free Survival (DFS) and Overall Survival (OS) in 66 AML treated on Hematology-Oncology Research Center, Iran, Tabriz. Results: The overall OS and EFS were 50% and 80.3% respectively during our study. Cox-regression analysis revealed that a poor EFS was significantly associated a low CD135 (HR 0.34, 95% CI 0.13–0.88, P = 0.02). Conclusion: This is the first study from Iran to show that the expressions of CD135, CD117 is easily measurable by routine diagnostic flow-cytometry, and CD135+117 were not significantly associated with CR, EFS, or OS .