Very late antigen-4 function of myeloblasts correlates with improved overall survival for patients with acute myeloid leukemia

Becker, Pamela S.; Kopecky, Kenneth J.; Wilks, Adrianne N.; Chien, Sylvia; Harlan, John M.; Willman, Cheryl L.; Petersdorf, Stephen H.; Stirewalt, Derek L.; Papayannopoulou, Thalia; Appelbaum, Frederick R.

doi:10.1182/blood-2007-12-124818

Cited by 64 publications

(44 citation statements)

References 35 publications

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“…In acute myeloid leukemia, more systematic studies have been published, with contradictory results, some finding that high VLA-4 expression was associated with adverse outcome 16,26 while others found that it was associated with improved outcome. 27,28 In our study of uniformly treated patients at first relapse, we observed that high VLA-4 expression was associated with an adverse outcome as well as with high-risk features, i.e. age, 29 immunophenotype and time of relapse.…”

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confidence: 76%

High VLA-4 expression is associated with adverse outcome and distinct gene expression changes in childhood B-cell precursor acute lymphoblastic leukemia at first relapse

Shalapour¹,

Hof²,

Kirschner-Schwabe³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundResistance to therapy and subsequent relapse remain major challenges in the clinical management of relapsed childhood acute lymphoblastic leukemia. As the bone marrow environment plays an important role in survival and chemotherapy resistance of leukemia cells by activating different signaling pathways, such as the VLA-4 and PI3K/Akt pathways, we studied the prognostic and biological impact of VLA-4 expression in leukemia cells from children with relapsed B-cell precursor acute lymphoblastic leukemia and its influence on the sensitivity of the leukemia cells to drugs. Design and MethodsVLA-4 expression was quantified by real-time polymerase chain reaction in leukemia cells from 56 patients with relapsed acute lymphoblastic leukemia enrolled in the ALL-REZ BFM 2002 trial of the Berlin-Frankfurt-Münster study group. Gene expression changes related to VLA-4 expression were investigated by microarray-based mRNA profiling. The effect of VLA-4 signaling on proliferation and drug resistance was studied in co-cultures of leukemia and stromal cells. ResultsHigh expression of VLA-4 at first relapse was associated with adverse prognostic factors, poor molecular response to therapy and significantly worse probabilities of event-free and overall survival. VLA-4 expression was an independent prognostic parameter. Comparing gene expression profiles of leukemia cells with high versus low VLA-4 expression, we identified 27 differentially expressed genes primarily involved in the PI3K/Akt, ephrin and Rho GTPase pathways. Blocking of VLA-4 signaling in combination with cytarabine treatment abolished the growth supportive effect of stromal cells. ConclusionsOur results show that high VLA-4 expression is a marker of poor prognosis and a potential therapeutic target in children with relapsed acute lymphoblastic leukemia and confirm that cellular interactions and biological effects related to VLA-4 play a decisive role in the survival of leukemia cells and response to therapy. (ClinicalTrials.gov identifier: NCT00114348)

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mentioning

confidence: 76%

High VLA-4 expression is associated with adverse outcome and distinct gene expression changes in childhood B-cell precursor acute lymphoblastic leukemia at first relapse

Shalapour¹,

Hof²,

Kirschner-Schwabe³

et al. 2011

Haematologica

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“…Increased expression of CXCR4 has also been associated with an increased risk of relapse and poor outcome in AML. 3,[5][6][7] A bicyclam small molecule antagonist of CXCR4 binding to CXCL12, plerixafor, is currently approved for clinical use in combination with G-CSF as a stem cell mobilizing agent for patients with multiple myeloma or non-Hodgkin lymphoma undergoing autologous HSCT. 8,9 We hypothesized that disrupting the CXCL12/CXCR4 axis with plerixafor may augment the effects of chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia

Uy¹,

Rettig²,

Motabi³

et al. 2012

Blood

353

311

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The interaction of acute myeloid leukemia (AML) blasts with the leukemic microenvironment is postulated to be an important mediator of resistance to chemotherapy and disease relapse. We hypothesized that inhibition of the CXCR4/CXCL12 axis by the small molecule inhibitor, plerixafor, would disrupt the interaction of leukemic blasts with the environment and increase the sensitivity of AML blasts to chemotherapy. In this phase 1/2 study, 52 patients with relapsed or refractory AML were treated with plerixafor in combination with mitoxantrone, etoposide, and cytarabine. In phase 1, plerixafor was escalated to a maximum of 0.24 mg/kg/d without any dose-limiting toxicities. In phase 2, 46 patients were treated with plerixafor 0.24 mg/kg/d in combination with chemotherapy with an overall complete remission and complete remission with incomplete blood count recovery rate (CR ؉ CRi) of 46%. Correlative studies demonstrated a 2-fold mobilization in leukemic blasts into the peripheral circulation. No evidence of symptomatic hyperleukocytosis or delayed count recovery was observed with the addition of plerixafor. We conclude that the addition of plerixafor to cytotoxic chemotherapy is feasible in AML, and results in encouraging rates of remission with correlative studies demonstrating in vivo evidence of disruption of the CXCR4/CXCL12 axis.

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“…1.0000 1.0000 1.0000 0.3800 1.0000 1.0000 1.0000 1.0000 0.5102 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 0.0318 1.0000 IL- 12 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 0.0604 1.0000 0.0993 1.0000 1.0000 1.0000 IL- 13 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 0.1719 1.0000 0.0993 1.0000 1.0000 1.0000 Age 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 Leu 1.0000 1.0000 1.0000 1.0000 1.0000 0.5601 1.0000 1.0000 0.2029 1.0000 0.0005 0.1011 0.0000 1.0000 1.0000 0.0318 1.0000 1.0000 1.0000 1.0000 CRP 1.0000 1.0000 0.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 0.3842 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 1.0000 (corrected P = 0.002). The correlation of IL-12 with IL-3 and IL-13 was close to statistical significance (P = 0.0604; P = 0.0993) after Bonferroni-Holm correction, the same as the correlation of IL-1α and IL-4 (P = 0.0609).…”

Section: Cytokines and Soluble Adhesion Molecules Levelsunclassified

“…Soluble (s) forms of adhesion molecules arise from proteolytic cleavage of surface-expressed molecules 11 . Increased binding of sVCAM-1 to α 4 β 1 integrin VLA-4 (Very Late Antigen-4) on myeloblasts was significantly associated with longer overall survival in newly diagnosed adult AML patients 12 .…”

Section: Introductionmentioning

confidence: 99%

Evaluation of cytokines and soluble adhesion molecules in patients with newly diagnosed acute myeloid leukemia: the role of TNF-alpha and FLT3-ITD

Kupsa¹,

Vaněk²,

Vašatová³

et al. 2016

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Objectives. Acute myeloid leukemia (AML) cells are highly resistant to therapy. The presumed molecular basis of this resistance is the effect of tumor necrosis factor alpha (TNF-α) and other cytokines on endothelial adhesion molecule expression. The aim of this study was to test the hypothesis that cytokines and soluble adhesion molecules correlate in AML. Methods. Baseline serum levels of 17 cytokines and 5 soluble adhesion molecules were measured in 53 AML patients using biochip array technology. Age, leukocyte count, secondary AML, CRP, FLT3-ITD and remission were variables. Statistical analysis was performed in R version 3.1.2. Results. VCAM-1 correlated with ICAM-1 (P < 0.0001), E-selectin (P < 0.0001), leukocyte count (P = 0.0005) and TNF-α (P = 0.0035). E-selectin correlated with leukocyte count (P < 0.0001), P-selectin (P = 0.0032) and MCP-1 (P = 0.0119). CRP correlated with IL-6 (P < 0.0001), leukocyte count negatively correlated with IL-7 (P = 0.0318). FLT3-ITD was associated with higher E-selectin (P = 0.0010) and lower IL-7 (P = 0.0252). Secondary AML patients were older. Failure of induction therapy was associated with significantly higher CRP and lower P-selectin. Leukocyte count (P < 0.0001), FLT3-ITD (P = 0.0017) and secondary AML (P = 0.0439) influenced the principal component. Conclusions. Leukemic cells can modulate the microenvironment. Cytokine, adhesion molecule levels and leukocyte count correlate in AML. Understanding these mechanisms may form the basis of novel therapeutic approaches.

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Very late antigen-4 function of myeloblasts correlates with improved overall survival for patients with acute myeloid leukemia

Cited by 64 publications

References 35 publications

High VLA-4 expression is associated with adverse outcome and distinct gene expression changes in childhood B-cell precursor acute lymphoblastic leukemia at first relapse

High VLA-4 expression is associated with adverse outcome and distinct gene expression changes in childhood B-cell precursor acute lymphoblastic leukemia at first relapse

A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia

Evaluation of cytokines and soluble adhesion molecules in patients with newly diagnosed acute myeloid leukemia: the role of TNF-alpha and FLT3-ITD

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