Restoration of in vitro hematopoiesis in B-chronic lymphocytic leukemia by antibodies to tumor necrosis factor

Michalevicz, Rita; Porat, Reuven; Vechoropoulos, Michal; Baron, Shoshana; Yanoov, M; Cycowitz, Zwi; Shibolet, Shlomo

doi:10.1016/0145-2126(91)90091-7

Cited by 21 publications

(13 citation statements)

References 24 publications

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“…Several cytokines, including TNF-α, produced by tumor and normal host cells contribute to the reduced erythropoiesis in chronic disease [4]. In vitro TNF-α seems to inhibit the formation of erythroid colonies [9, 10]as well as the production of Epo [11, 12, 13]. Some reports suggest that in vivo TNF-α reduces Epo production [26]and suppresses Epo-dependent erythropoiesis [27, 28].…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of Tumor Necrosis Factor-α and Erythropoietin Serum Levels in B-Cell Chronic Lymphocytic Leukemia Patients with Anemia

Capalbo

Battista²,

Delia³

et al. 2002

Acta Haematol

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Serum levels of tumor necrosis factor-α (TNF-α) and of erythropoietin (Epo) have been evaluated in 100 patients with B-cell chronic lymphocytic leukemia (CLL) in order to determine whether these factors could be significant in the development of anemia, which was observed in some cases with advanced disease. In our series of patients, TNF-α serum levels had an inverse correlation with hemoglobin levels (r = –0.813). In patients with anemia, the serum levels of TNF-α were significantly higher (p = 0.022) than in those without anemia (186.7 ± 84.7 vs. 39.8 ± 20.7 pg/ml). Serum Epo levels were also significantly (p = 0.0003) increased in CLL patients with anemia compared to those without (134.1 ± 225.9 vs. 12.3 ± 4.8 mU/ml). The ratio of observed/predicted (O/P) serum Epo was adequate (>0.8) for the degree of anemia in 70% of patients with anemia and inadequate in the remaining 30%. In the latter, the mean serum TNF-α level was significantly higher (p = 0.005) than the mean for the anemic cases with an adequate O/P ratio of serum Epo (234.1 vs. 166.4 pg/ml). These data suggest that although CLL anemia is not characterized by inadequate Epo production, in some CLL patients this factor may be correlated. In these cases, the levels of TNF-α were significantly higher than in other anemic cases. Compared to other CLL patients with anemia, these CLL patients might better respond to therapy with recombinant human Epo in pharmacological doses.

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Section: Discussionmentioning

confidence: 99%

“…Increased serum (s) TNF-α levels are associated with anemia in cancer patients with advanced-stage diseases [7, 8]. Moreover, in vitro TNF-α seems to inhibit the formation of human erythroid colonies [9, 10]as well as the production of Epo [11, 12, 13]. …”

Section: Introductionmentioning

confidence: 99%

Evaluation of Tumor Necrosis Factor-α and Erythropoietin Serum Levels in B-Cell Chronic Lymphocytic Leukemia Patients with Anemia

Capalbo

Battista²,

Delia³

et al. 2002

Acta Haematol

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“…Particularly, CLL cells may produce Tumor Necrosis Factor (TNF)-alpha, which can inhibit growth of hematopoietic cells in vitro (17,18). Also, CLL patients with disease-associated anemia have been noted to have higher serum levels of TNF-alpha than CLL patients without anemia, suggesting that TNF-alpha may be at least in part responsible for the cytopenias observed in some patients with CLL (18).…”

Section: Impact Of Cll Cells On the Hematopoietic Nichementioning

confidence: 99%

Structure and function of the hematopoietic cancer niche focus on chronic lymphocytic leukemia

Kipps¹

2012

Front Biosci

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Chronic Lymphocytic Leukemia (CLL) is a B cell malignancy characterized by the accumulation of mature monoclonal CD5-positive B cells in the blood, secondary lymphoid tissues, and marrow. The infiltration of CLL cells in lymphoid tissues is a key element of disease pathogenesis. It is in such tissues that are found the microenvironments that provide CLL cells protection from spontaneous and/or drug-induced apoptosis. CLL cells actively shape their microenvironment by producing cytokines and chemokines, and by subverting normal accessory cells to promote leukemia-cell survival, proliferation, and escape from immune detection. In this review, we discuss how CLL cells disrupt the niches required for normal hematopoiesis or immune function and subvert normal cells in the microenvironment to support neoplastic cell growth and survival.

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“…Importantly, dysregulated, sustained expression of GATA-1 can inhibit erythroid differentiation 12, 13 . BM infiltration of CLL cells, which constitutively produce TNFα 14, 15 , may further inhibit erythropoiesis by introducing TNFα to the hematopoietic niche and altering the balance between transcription factors expressed in HSPCs, particularly PU.1 and GATA-2. Cumulatively, based on these published findings and with the goal of better understanding the etiology of immune dysfunction in CLL, we assessed BM HSPC functional capacity and performed an in-depth characterization of hematopoietic progenitor subsets in untreated CLL patients.…”

Section: Introductionmentioning

confidence: 99%

Bone marrow hematopoietic dysfunction in untreated chronic lymphocytic leukemia patients

et al. 2018

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The consequences of immune dysfunction in B-Chronic Lymphocytic Leukemia (CLL) likely relate to the incidence of serious recurrent infections and second malignancies that plague CLL patients. The well-described immune abnormalities are not able to consistently explain these complications. Here, we report bone marrow (BM) hematopoietic dysfunction in early and late stage untreated CLL patients. Numbers of CD34+ BM hematopoietic progenitors responsive in standard CFU assays, including CFU-GM/GEMM and CFU-E, were significantly reduced. Flow cytometry revealed corresponding reductions in frequencies of all hematopoietic stem and progenitor cell (HSPC) subsets assessed in CLL patient marrow. Consistent with the reduction in HSPCs, BM resident monocytes and natural killer (NK) cells were reduced, a deficiency recapitulated in blood. Finally, we report increases in protein levels of the transcriptional regulators HIF-1α GATA-1, PU.1, and GATA-2 in CLL patient BM, providing molecular insight into the basis of HSPC dysfunction. Importantly, PU.1 and GATA-2 were rapidly increased when healthy HSPCs were exposed in vitro to TNFα, a cytokine constitutively produced by CLL B cells. Together, these findings reveal BM hematopoietic dysfunction in untreated CLL patients that provides new insight into the etiology of the complex immunodeficiency state in CLL.

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Restoration of in vitro hematopoiesis in B-chronic lymphocytic leukemia by antibodies to tumor necrosis factor

Cited by 21 publications

References 24 publications

Evaluation of Tumor Necrosis Factor-α and Erythropoietin Serum Levels in B-Cell Chronic Lymphocytic Leukemia Patients with Anemia

Evaluation of Tumor Necrosis Factor-α and Erythropoietin Serum Levels in B-Cell Chronic Lymphocytic Leukemia Patients with Anemia

Structure and function of the hematopoietic cancer niche focus on chronic lymphocytic leukemia

Bone marrow hematopoietic dysfunction in untreated chronic lymphocytic leukemia patients

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