Sensitivity of human multiple myelomas and myeloid leukemias to the proteasome inhibitor I

Servida, Federica; Soligo, Davide; Delia, Domenico; Henderson, Clare; Brancolini, Claudio; Lombardi, Luigia; Deliliers, Giorgio Lambertenghi

doi:10.1038/sj.leu.2403987

Cited by 33 publications

(30 citation statements)

References 41 publications

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“…These studies used BCR-ABL ϩ cell lines both sensitive and resistant to IM and demonstrated antiproliferative and apoptotic effects. [39][40][41] In addition, the PI Z-Ile-Glu(OtBu)-Ala-Leucinal selectively inhibits colony formation by CD34 ϩ BCR-ABL ϩ progenitor cells. 41 Despite promising in vitro effects, there are little in vivo data.…”

Section: Introductionmentioning

confidence: 99%

Bortezomib induces apoptosis in primitive chronic myeloid leukemia cells including LTC-IC and NOD/SCID repopulating cells

Heaney

Pellicano

Zhang

et al. 2010

Blood

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Section: Introductionmentioning

confidence: 99%

Bortezomib induces apoptosis in primitive chronic myeloid leukemia cells including LTC-IC and NOD/SCID repopulating cells

Heaney

Pellicano

Zhang

et al. 2010

Blood

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“…The lack of down-regulation of HLA class I on CD34 ϩ and healthy cells is consistent with reports that MM is significantly more sensitive to proteasome inhibition compared with CD34 ϩ bone marrow progenitor cells. 42,43 A single dose of bortezomib also down-regulated HLA class I on CD138-purified MM cells in vivo. We confirmed that HLA-C was equally down-regulated because HLA-C is the principal inhibitory ligand for KIR on NK cells.…”

mentioning

confidence: 99%

Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell–mediated lysis of myeloma

Shi¹,

Tricot²,

Garg³

et al. 2008

Blood

162

128

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IntroductionMultiple myeloma (MM) is a prototypic B-cell malignancy with overall survival varying from a few months to more than 15 years with melphalan-based autologous stem cell transplantation. 1 It is well established that patients with abnormal, especially hypodiploid karyotypes, and high lactic dehydrogenase have a worse prognosis. 2 Recently, we have reported that approximately 13% of MM patients have a high-risk prognostic score defined by the differential expression of 70 key genes, many of which are located on chromosome 1. 3 These patients have a poor outcome compared with low-risk patients, with inferior actuarial event-free survival (18% vs 60%, hazard ratio (HR) ϭ 4.51) and overall survival (28% vs 78%, HR ϭ 5.16) at 5 years despite intensive treatment on total therapy tandem transplantation regimens and the incorporation of novel agents, such as bortezomib into up-front management. 3 There is therefore a need for novel treatment approaches that target the melphalan-refractory myeloma stem cell pool in high-risk patients and synergize with currently available cytoreductive regimens.Killer-cell immunoglobulin-like receptor (KIR)-ligand (KIR-L) mismatched natural killer (NK) cells have potent antileukemic effects in the setting of heavily T cell-depleted haplo-identical allogeneic transplantation, but the majority of MM patients cannot tolerate the associated toxicity of such regimens. 4 However, we have recently demonstrated in a pilot trial that T cell-depleted haplo-identical KIR-L mismatched NK cells can be safely given to high-risk MM patients in the setting of an autologous transplantation without evidence of graft-versus-host disease. 5 Unfortunately, not all NK cells transfused are alloreactive; indeed, the majority are inhibited by patient human leukocyte antigen (HLA) class I, particularly HLA-C and -Bw4 molecules. 6 NK-cell activity is regulated by a dynamic balance between inhibitory and activating receptors that recognize ligands on target cells, with the inhibitory signals typically being dominant to prevent destruction by NK cells of healthy cells. [7][8][9][10][11] It has been postulated that mature NK cells express at least one inhibitory receptor for autologous HLA class I, thus preserving self-tolerance. In contrast, NK cells avidly lyse tumor cells that do not display such inhibitory KIR-L. A classic example is the cell line K562, which does not express HLA class I.HLA class I molecules consist of a major histocompatibility complex-encoded heavy chain, the light chain ␤ 2 -microglobulin (␤ 2 M), 12 and a third subunit, a peptide of 8 to 10 amino acids. 12,13 In humans, class I heavy chains are encoded by 3 loci, HLA-A, -B, and -C. The proteasome is responsible for the generation of peptides, which are transported to the endoplasmic reticulum. There they combine with HLA class I and ␤ 2 M, and are transported to the cell surface via the Golgi apparatus. 14 Binding of peptides to HLA class I is essential for the stability of HLA class I at the cell surface. HLA class I molecules/␤ 2...

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“…Bortezomib has been approved for treatment of multiple myeloma progressing on prior therapy. 4,9 Selective induction of cell death mediated by proteasome inhibition has been well documented in various malignancies, among them multiple myeloma, ovarian cancers, leukemias, and T and B cell lymphomas. 4,10 However, the effects of proteasome inhibition on non-malignant developing and mature lymphocytes remain largely unknown.…”

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confidence: 99%

Proteasome inhibition drastically but reversibly impairs murine lymphocyte development

et al. 2008

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The proteasome inhibitor bortezomib, which induces cell death in various cancer cell lines including lymphatic neoplasias, has recently been approved for the treatment of relapsed multiple myeloma. Important mechanisms of proteasome inhibitormediated tumor cell death are the inhibition of NF-jB activation and induction of the terminal unfolded protein response (UPR). However, little is known about effects of bortezomib on developing and mature lymphocytes. Therefore, Balb/C mice were injected with bortezomib and lymphocyte subsets were analyzed. This treatment resulted in dramatically decreased numbers of T and B lymphocyte precursors, while mature lymphocytes were only partially affected. Thymocytes were almost depleted 3 days after a single bortezomib injection, pro-B and pre-B cells already after 2 days. Thymocytes and B cell precursors recovered within 2 weeks. The decreased numbers of developing lymphocytes were due to apoptotic cell death accompanied by strongly increased caspase 3/7 activity. Within 8 h after bortezomib injection, there was a strong induction of heat shock protein 70 and C/ EBP homologous protein in bone marrow B cells, indicating endoplasmic reticulum stress and activation of the terminal UPR, respectively. Hence, induction of apoptosis by proteasome inhibition can dramatically affect lymphocyte development, a fact which has important implications for the clinical use of bortezomib, especially in situations with ongoing lymphopoiesis.

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Sensitivity of human multiple myelomas and myeloid leukemias to the proteasome inhibitor I

Cited by 33 publications

References 41 publications

Bortezomib induces apoptosis in primitive chronic myeloid leukemia cells including LTC-IC and NOD/SCID repopulating cells

Bortezomib induces apoptosis in primitive chronic myeloid leukemia cells including LTC-IC and NOD/SCID repopulating cells

Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell–mediated lysis of myeloma

Proteasome inhibition drastically but reversibly impairs murine lymphocyte development

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