Defective blood dendritic cells in chronic myeloid leukemia correlate with high plasmatic VEGF and are not normalized by imatinib mesylate

Boissel, Nicolas; Rousselot, Philippe; Raffoux, Emmanuel; Jm, Cayuela; Maarek, Odile; Charron, Dominique; Degos, Laurent; Dombret, Hervé; Toubert, Antoine; Réa, Delphine

doi:10.1038/sj.leu.2403474

Cited by 82 publications

(79 citation statements)

References 29 publications

(28 reference statements)

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“…Given that IRF8 is essential for the development of DCs, another intriguing possibility is the antagonistic relationship between IRF8 and BCR-ABL in DC biology. In fact, DC counts in the peripheral blood of CML patients are significantly lower than in healthy individuals [72,73]. Our study, which used a mouse CML model, revealed that the suppression of Irf8 by BCR-ABL is the cause of DC deficiency in CML [74]; the forced expression of IRF8 overrides BCR-ABL to rescue DC development.…”

Section: As Already Mentioned Irf8mentioning

confidence: 92%

Regulation of myelopoiesis by the transcription factor IRF8

2015

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Section: As Already Mentioned Irf8mentioning

confidence: 92%

Regulation of myelopoiesis by the transcription factor IRF8

2015

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“…2D) is consistent with a recent study (33) suggesting that drug treatment might decrease effector function through indirect effects on inflammation or non-T cells such as APCs. In this regard, some studies had suggested that imatinib negatively affected DC numbers and function (10,36). However, 2 weeks of imatinib did not alter DC numbers or expression of MHC class II, B7-2 and IL-12p40 (37) (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that imatinib treatment can result in impaired adaptive and innate immunity including T cell, dendritic cell (DC), and monocytes/macrophages function (10). Notably, several investigators have demonstrated antiinflammatory effects in various mouse models.…”

mentioning

confidence: 99%

Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice

Louvet

Szot

Lang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

200

191

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The recent development of small-molecule tyrosine kinase (TK) inhibitors offers increasing opportunities for the treatment of autoimmune diseases. In this study, we investigated the potential of this new class of drugs to treat and cure type 1 diabetes (T1D) in the NOD mouse. Treatment of prediabetic and new onset diabetic mice with imatinib (Gleevec) prevented and reversed T1D. Similar results were observed with sunitinib (Sutent), an additional approved multikinase inhibitor, suggesting that the primary target of imatinib, c-Abl, was not essential in blocking disease in this model. Additional studies with another TK inhibitor, PLX647 (targeting c-Kit and c-Fms) or an anti-c-Kit mAb showed only marginal efficacy whereas a soluble form of platelet-derived growth factor receptor (PDGFR), PDGFR␤Ig, rapidly reversed diabetes. These findings strongly suggest that inhibition of PDGFR is critical to reverse diabetes and highlight a crucial role of inflammation in the development of T1D. These conclusions were supported by the finding that the adaptive immune system was not significantly affected by imatinib treatment. Finally, and most significantly, imatinib treatment led to durable remission after discontinuation of therapy at 10 weeks in a majority of mice. Thus, long-term efficacy and tolerance is likely to depend on inhibiting a combination of tyrosine kinases supporting the use of selective kinase inhibitors as a new, potentially very attractive approach for the treatment of T1D.autoimmunity ͉ diabetes ͉ tyrosine kinase inhibitor ͉ imatinib ͉ PDGFR

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“…Chronic myeloid leukemia (CML) is a clonal disease, characterized by a reciprocal t (9,22) chromosomal translocation resulting in a chimeric BCR/ABL fusion gene that encodes an abnormal fusion protein (p210) with a tyrosine kinase activity, which probably plays a key role in the pathogenesis of the disease [5]. Imatinib mesylate is a specific inhibitor of of Abl protein tyrosine kinases, which has been shown to induce complete hematologic and cytogenetic responses in a significant proportion of patients [6] and has become the standard first-line treatment for patients with chronic phase CML (CP-CML).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of monocyte-derived dendritic cells, T regulatory and Th17 cells in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors

Hus

Tabarkiewicz²,

Lewandowska³

et al. 2011

Folia Histochem Cytobiol.

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Abstract:Immunotherapy with dendritic cells (DC) may constitute a new and advantageous option for patients with chronic myeloid leukemia (CML) who respond to therapy with tyrosine kinase inhibitors (TKI), but do not reach complete cytogenetic or molecular remission. In this study, we evaluated the immunophenotype of DC generated from monocytes (Mo-DC) of patients with CML and the influence of TKI therapy on the results of CML-DC generation. We also measured the percentages of T regulatory cells (Tregs) as well as Th17 cells in 19 untreated patients suffering from CML, and in 28 CML patients treated with TKI. We found that DC can be reliably generated from the peripheral blood CD14 + cells of untreated CML patients. But we observed a persistent expression of CD14 monocyte marker on DC from CML patients, together with lower percentages of Mo-DC with expression of CD1a (p = 0.002), CD80 (p = 0.0005), CD83 (p = 0.0004), and CD209 (p = 0.02) compared to healthy donors. There was an adverse correlation between WBC count and the percentage of Mo-DC with co-expression of CD80 and CD86 (R = -0.63; p = 0.03). In patients treated with TKI, we observed higher efficacy of DC generation in seven-day cultures, compared to untreated patients. Expression of CD209 on DC was higher in patients treated with TKI (0.02). The duration of TKI therapy correlated adversely with MFI for CD1a (R = -0.49; p = 0.006) and positively with MFI for CD83 (R = 0.63; p = 0.01). Percentages of CD4 + CD25 high FoxP3 + cells (p = 0.0002) and Th17 cells (p = 0.02) were significantly higher in untreated CML patients compared to healthy controls. There was a significant correlation between the percentage of Treg cells and the percentage of peripheral blood basophiles (R = 0.821; p = 0.02). There were no changes in Tregs or Th17 cell percentages in CML patients after six months of TKI therapy. However, the expression of intracellular IL-17 in Th17 cells correlated negatively with the time of TKI therapy in the whole group of treated patients (R = -0.516; p = 0.04). We noted a correlation between IL-6 serum level and peripheral blood WBC count (R = 0.492; p = 0.04). There was also an inverse correlation between the serum level of IL-6 and the duration of TKI therapy (R = -0.66; p = 0.03). Taken together, our data shows that mature DC can be generated from CML patients treated with TKI, and that the yield of Mo-DC is higher in patients treated with TKI than in patients with active disease. This should encourage further trials with DC immunotherapy in patients with cytogenetic response after TKI therapy. We also found increased frequencies of T regulatory and Th17 cells in CML patients, which might suggest their potential role in immunity against 154

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Defective blood dendritic cells in chronic myeloid leukemia correlate with high plasmatic VEGF and are not normalized by imatinib mesylate

Cited by 82 publications

References 29 publications

Regulation of myelopoiesis by the transcription factor IRF8

Regulation of myelopoiesis by the transcription factor IRF8

Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice

Evaluation of monocyte-derived dendritic cells, T regulatory and Th17 cells in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors

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