Abstract:
:Future progress in the treatment of multiple myeloma (MM) requires both the characterisation of key drivers of the disease and novel, innovative approaches to tackle these vulnerabilities. The present study focussed on the pre-clinical evaluation of a novel drug class, BMI-1 modulators, in MM. We demonstrate potent activity of PTC-028 and PTC596 in a comprehensive set of in vitro and in vivo models, including models of drug resistance and stromal support. Treatment of MM cells with PTC-028 and PTC596 downregulated BMI-1 protein levels, which was found to correlate with drug activity. Surprisingly, BMI-1 was dispensable for the activity of BMI-1 modulators and MM cell growth. Our data rather point to mitotic arrest accompanied by myeloid cell leukaemia-1 (MCL-1) loss as key anti-MM mechanisms and reveal impaired MYC and AKT signalling activity due to BMI-1 modulator treatment. Moreover, we observed a complete eradication of MM after PTC596 treatment in the 5TGM.1 in vivo model and define epigenetic compounds and B cell leukaemia/lymphoma 2 homology domain 3 (BH3) mimetics as promising combination partners. These results bring into question the postulated role of BMI-1 as an essential MM gene and confirm BMI-1 modulators as potent anti-mitotic agents with encouraging pre-clinical activity that supports their rapid translation into clinical trials.
journal_name
Br J Haematoljournal_title
British journal of haematologyauthors
Bolomsky A,Muller J,Stangelberger K,Lejeune M,Duray E,Breid H,Vrancken L,Pfeiffer C,Hübl W,Willheim M,Weetall M,Branstrom A,Zojer N,Caers J,Ludwig Hdoi
10.1111/bjh.16595subject
Has Abstractpub_date
2020-09-01 00:00:00pages
877-890issue
6eissn
0007-1048issn
1365-2141journal_volume
190pub_type
杂志文章abstract::A child of Italian origin with a congenital haemolytic anaemia had spectrophotometrically undetectable erythrocyte adenylate kinase (AK) activity. Her parents and brother had approximately 50% normal AK activity, and AK electrophoresis of red blood cell (RBC) crude extract on cellulose acetate strips showed the presen...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1997.4953299.x
更新日期:1997-12-01 00:00:00
abstract::We report on a case of pyridoxine refractory hereditary sideroblastic anaemia (HSA) in a 19-year-old man who underwent peripheral blood stem cell transplantation (PBSCT) from his HLA-identical brother. By using short tandem repeat polymorphism, 100% donor cells were observed in peripheral blood on day +21; bone marrow...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.2000.02050.x
更新日期:2000-06-01 00:00:00
abstract::Site-specific deletions of the 5' part of the TAL1 gene (tal(d)) are among the most frequent non-random genetic abnormalities in T-cell acute lymphoblastic leukaemia (T-ALL). They are usually detected by PCR from DNA with several primer pairs or by Southern blot analysis. Since tal(d) lead to expression of a SIL-TAL1 ...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1997.4833286.x
更新日期:1997-12-01 00:00:00
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journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.2003.04535.x
更新日期:2003-09-01 00:00:00
abstract::The administration of Interleukin-2 (IL-2) causes the release or generation of other cytokines such as tumour necrosis factor (TNF) which, by disturbing the anticoagulant properties of the endothelium, may induce a procoagulant state in patients receiving this drug. We therefore evaluated the effects of IL-2 on coagul...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1992.tb06421.x
更新日期:1992-10-01 00:00:00
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journal_title:British journal of haematology
pub_type: 杂志文章,评审
doi:10.1111/j.1365-2141.2010.08325.x
更新日期:2010-11-01 00:00:00
abstract::Hepatitis B virus (HBV) reactivation of various degrees of severity, including fulminant hepatitis, may develop in 20-50% of hepatitis B virus surface antigen (HbsAg)-positive patients undergoing immunosuppressive or cytostatic treatment. Lamivudine is a nucleoside analogue that can directly suppress HBV replication. ...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.2001.03099.x
更新日期:2001-10-01 00:00:00
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journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1984.tb02190.x
更新日期:1984-04-01 00:00:00
abstract::We report the characterization of three variant antithrombins with reduced heparin binding as the primary abnormality. Two of these variants, antithrombin Southport (Leu 99 to Val, 2759 C to G) and antithrombin Vienna (Gln 118 to Pro, 5349 A to C) were novel, whereas the third, Pro 41 to Leu, has been previously descr...
journal_title:British journal of haematology
pub_type: 杂志文章
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更新日期:1995-03-01 00:00:00
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journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1983.tb01246.x
更新日期:1983-10-01 00:00:00
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journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.2008.07266.x
更新日期:2008-11-01 00:00:00
abstract::The prognosis of paediatric acute myeloid leukaemia (AML) with primary induction failure (PIF) is extremely poor, and effective treatment strategies have not been established. We investigated the clinical and biological features of paediatric AML patients with PIF registered to the Japanese Paediatric Leukaemia/Lympho...
journal_title:British journal of haematology
pub_type: 杂志文章,多中心研究
doi:10.1111/bjh.15799
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journal_title:British journal of haematology
pub_type: 杂志文章,评审
doi:10.1111/j.1365-2141.2011.09013.x
更新日期:2012-03-01 00:00:00
abstract::Liposomes prepared from rabbit brain extracts (RBE) and individual pure lipids (high phosphatidyl serine content, HIPS) were compared with frozen-thawed platelets (PLTS) in the dilute Russell Viper venom time (dRVVt). While all three preparations demonstrated sensitivity to lupus anticoagulant (LA) the highest detecti...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1994.tb04790.x
更新日期:1994-03-01 00:00:00
abstract::A 30-year-old woman was diagnosed as having an acute promyelocytic leukaemia in September 1981. Chemotherapeutic courses of daunomycin, ara-C, thioguanine and prednisolone were administered, resulting in a complete remission. A relapse occurred in January 1982, and chemotherapy did not lead to a second complete remiss...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1984.tb02910.x
更新日期:1984-07-01 00:00:00
abstract::This study investigated the response of acute lymphoblastic leukaemia (ALL) cells to Wnt proteins. Accumulation of beta-catenin was measured by Western blotting and immunofluorescence microscopy. Reverse transcription polymerase chain reaction (RT-PCR) analysis of B-cell progenitor acute lymphoblastic leukaemia (ALL) ...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.2007.06667.x
更新日期:2007-08-01 00:00:00
abstract::Antithrombin III (AT III) activity has been measured in 9669 healthy blood donors (5525 male and 4144 female). The distribution of AT III is approximately 'normal' with mean 105.6 IU/dl and standard deviation 11.2; however, definite age and sex related variations are evident. Pre-menopausal females have lower mean AT ...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1993.tb03104.x
更新日期:1993-07-01 00:00:00
abstract::The pathogenesis of HELLP (haemolysis, elevated liver enzyme and low platelet count) syndrome, a severe presentation of pre-eclampsia, is still an enigma. Activated protein C resistance resulting from a mutation in coagulation factor V has recently emerged as the leading cause of thrombosis in pregnancy. We report on ...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1996.410947.x
更新日期:1996-03-01 00:00:00
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journal_title:British journal of haematology
pub_type: 杂志文章
doi:
更新日期:2000-12-01 00:00:00
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journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/bjh.15239
更新日期:2018-06-01 00:00:00
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journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.2000.02359.x
更新日期:2000-11-01 00:00:00
abstract::The humanized CD52 monoclonal antibody Campath-1H was used as first-line therapy in nine patients with progressive chronic lymphocytic leukaemia (CLL). Intravenous (n = 5) or subcutaneous (n = 4) injections (up to 30 mg/inj.) were given three times a week for a maximum of 18 weeks. Three patients achieved a complete r...
journal_title:British journal of haematology
pub_type: 临床试验,杂志文章
doi:10.1046/j.1365-2141.1996.450989.x
更新日期:1996-04-01 00:00:00
abstract::Immune reconstitution was studied prospectively in 66 children who underwent 77 haematopoietic cell transplantations (HCT): 46 autologous HCTs in 39 patients and 31 allogeneic HCTs in 27 patients. We studied the dynamic analysis of immune recovery with regard to potential factors affecting its speed, including age, ty...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.2002.03560.x
更新日期:2002-07-01 00:00:00
abstract::In a prospective phase II trial, pentostatin combined with cyclophosphamide and rituximab (PCR) induced strong responses and was well-tolerated in previously untreated patients with advanced-stage, indolent non-Hodgkin lymphoma (iNHL). After a median patient follow-up of more than 108 months, we performed an intent-to...
journal_title:British journal of haematology
pub_type: 杂志文章,随机对照试验
doi:10.1111/bjh.15814
更新日期:2019-05-01 00:00:00
abstract::The erythrocyte chemokine receptor, a receptor for Plasmodium vivax, carries the antigens of the Duffy blood group system. Sequence analysis of reticulocyte RNA from individuals of known Duffy phenotype showed that the Fya antigen differs from the Fyb antigen as a result of a single nucleotide difference (A131 or G) e...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1995.tb05202.x
更新日期:1995-08-01 00:00:00
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journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1995.tb05308.x
更新日期:1995-10-01 00:00:00
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journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1998.00631.x
更新日期:1998-03-01 00:00:00
abstract::A new, in-line high-efficiency 3-5 log10 leucodepletion filter system (Leukotrap RC system) was used to investigate the effect of pre-storage white cell removal on the quality of AS-3 red cell concentrates stored for 42 d at 4 degrees C. Median residual white cell content was 4 x 10(5) when filtration was performed at...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1994.tb04923.x
更新日期:1994-06-01 00:00:00
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journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1995.tb08901.x
更新日期:1995-01-01 00:00:00
abstract::To investigate the role of neutrophils in complement-induced changes in vascular permeability, skin wheal and flare responses to intradermal injection of autologous activated serum complement were measured in normal and neutropenic subjects. In normal subjects, responses were dose-dependent and were abolished by remov...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1986.tb04131.x
更新日期:1986-10-01 00:00:00