Biological Significance of Proliferation, Apoptosis, Cytokines, and Monocyte/Macrophage Cells in Bone Marrow Biopsies of 145 Patients With Myelodysplastic Syndrome

Allampallam, Krishnan; Shetty, Vilasini; Mundle, Suneel; Dutt, Diya; Kravitz, Howard M.; Reddy, Poluru L.; Alvi, Sairah; Galili, Naomi; Saberwal, Gurveen; Anthwal, Shalini; Shaikh, Maliha; York, Aaron; Raza, Azra

doi:10.1007/bf02982044

Cited by 79 publications

(50 citation statements)

References 29 publications

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“…25 Instead, it is possible that cytokines such as TGF-b, known to downregulate the surface expression of NKG2D and detected in high levels in patients with MDS, may be involved in the reduced expression of NKG2D. 39,40 Recently, increasing knowledge on the molecular specificities for NK-cell activation has been gained from experiments in reductionistic model systems. 18 Emerging evidence suggests that resting NK cells require signaling through multiple activating receptors simultaneously to induce natural cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Reduced DNAM-1 expression on bone marrow NK cells associated with impaired killing of CD34+ blasts in myelodysplastic syndrome

Carlsten

Simonsson

et al. 2010

Leukemia

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Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal stem-cell disorders characterized by ineffective hematopoiesis and risk of progression to acute myeloid leukemia. Increased apoptosis and suppressed functions of peripheral blood natural killer (NK) cells have been described in MDS patients, but only limited information is available on the phenotypic and functional integrity of NK cells in the bone marrow. In a cohort of 41 patients with distinct clinical subtypes of MDS, we here show that NK cells in the bone marrow show decreased surface expression of the activating receptors DNAM-1 and NKG2D. Notably, decreased receptor expression correlated with elevated bone marrow blast counts and was associated with impaired NK-cell responsiveness to stimulation with the K562 cell line, or co-activation by NKG2D or DNAM-1 in combination with the 2B4 receptor. Furthermore, antibodymasking experiments revealed a central role for DNAM-1 in NK cell-mediated killing of freshly isolated MDS blasts. Thus, given the emerging evidence for NK cell-mediated immune surveillance of neoplastic cells, we speculate that reduced expression of DNAM-1 on bone marrow NK cells may facilitate disease progression in patients with MDS.

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Section: Discussionmentioning

confidence: 99%

Reduced DNAM-1 expression on bone marrow NK cells associated with impaired killing of CD34+ blasts in myelodysplastic syndrome

Carlsten

Simonsson

et al. 2010

Leukemia

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“…One such disorder is chronic myelomonocytic leukemia (CMML), originally categorized as MDS (18), but recently reclassified by the World Health Organization as a distinct entity (19). Indeed, ex vivo studies showed low TNF␣ levels in patients with CMML (20)(21)(22).…”

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confidence: 99%

Dysregulation of IL-32 in myelodysplastic syndrome and chronic myelomonocytic leukemia modulates apoptosis and impairs NK function

Marcondes

Mhyre

Stirewalt

et al. 2008

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

121

107

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TNF␣ levels are elevated in the marrows of patients with myelodysplastic syndrome (MDS) and are associated with high rates of apoptosis, which contributes to hematopoietic failure. We observed that exposure of human marrow stroma cell lines HS5 and HS27a to TNF␣ increases levels of IL-32 mRNA. IL-32, in turn, induces TNF␣. Marrow stroma from patients with MDS expressed 14-to 17-fold higher levels of IL-32 mRNA than healthy controls. In contrast, cells from patients with chronic myelomonocytic leukemia (CMML) expressed only one tenth the level of IL-32 measured in healthy controls. Human KG1a leukemia cells underwent apoptosis when cocultured with HS5 stromal cells, but knockdown of IL-32 in the stromal cells by using siRNA abrogated apoptosis in the leukemia cells. IL-32 knockdown cells also showed dysregulation of VEGF and other cytokines. Furthermore, CD56 ؉ natural killer cells from patients with MDS and CMML expressed IL-32 at lower levels than controls and exhibited reduced cytotoxic activity, which was unaffected by IL-2 treatment. We propose that IL-32 is a marrow stromal marker that distinguishes patients with MDS and CMML. Furthermore, IL-32 appears to contribute to the pathophysiology of MDS and may be a therapeutic target. marrow stroma ͉ TNF␣

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“…In the siltuximab group, the mean platelet count decreased from baseline (227. 6 ]; 21%). However, the incidence of thrombocytopenia was low and comparable between the two treatment groups (siltuximab group: 6%; placebo group: 4%).…”

Section: Safetymentioning

confidence: 99%

“…In many patients with MDS, levels of pro-inflammatory cytokines, such as tumor necrosis factor-a (TNF-a), transforming growth factor-b (TGF-b), and interleukin-6 (IL-6), are elevated compared to healthy persons or patients with other forms of marrow failure [2][3][4][5][6][7]. In particular, IL-6 may play an important role in the pathophysiology of anemia of inflammation associated with MDS as co-stimulator of in vitro progenitor growth and mediator of disease progression in MDS [2,8,9].…”

Section: Introductionmentioning

confidence: 99%

A phase 2, randomized, double‐blind, multicenter study comparing siltuximab plus best supportive care (BSC) with placebo plus BSC in anemic patients with International Prognostic Scoring System low‐ or intermediate‐1–risk myelodysplastic syndrome

et al. 2014

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Interleukin-6 (IL-6) may play an important role in the pathophysiology of anemia of inflammation associated with myelodysplastic syndrome (MDS). This double-blind, placebo-controlled, phase 2 study assessed the efficacy and safety of siltuximab, a chimeric anti-IL-6 monoclonal antibody, in patients with low-and intermediate-1-risk MDS who require transfusions for MDS anemia. Patients were randomized in a 2:1 ratio to siltuximab 15 mg kg 21 every 4 weeks 1 best supportive care (BSC) or placebo 1 BSC for 12 weeks. The primary endpoint was reduction in red blood cell (RBC) transfusions to treat MDS anemia, defined as 50% relative decrease and 2-unit absolute decrease in RBC transfusions. Fifty and 26 patients were randomized to the siltuximab and placebo groups, respectively. The study did not meet its prespecified hypothesis, with six (12%) patients in the siltuximab group and one (3.8%) in the placebo group having reductions in RBC transfusions (P 5 0.271). At the time of the planned futility analysis, the prespecified cutoff criteria were not met, and the study was terminated early due to lack of efficacy. No unexpected safety findings were observed. In conclusion, compared to placebo, treatment with siltuximab did not reduce RBC transfusions in transfusion-dependent patients with low-and intermediate-1-risk MDS. Future studies might explore siltuximab in patients with less iron overload and with elevated IL-6 levels and/or using higher doses for MDS.

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Biological Significance of Proliferation, Apoptosis, Cytokines, and Monocyte/Macrophage Cells in Bone Marrow Biopsies of 145 Patients With Myelodysplastic Syndrome

Cited by 79 publications

References 29 publications

Reduced DNAM-1 expression on bone marrow NK cells associated with impaired killing of CD34+ blasts in myelodysplastic syndrome

Reduced DNAM-1 expression on bone marrow NK cells associated with impaired killing of CD34+ blasts in myelodysplastic syndrome

Dysregulation of IL-32 in myelodysplastic syndrome and chronic myelomonocytic leukemia modulates apoptosis and impairs NK function

A phase 2, randomized, double‐blind, multicenter study comparing siltuximab plus best supportive care (BSC) with placebo plus BSC in anemic patients with International Prognostic Scoring System low‐ or intermediate‐1–risk myelodysplastic syndrome

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