Small molecule MIRA-1 induces in vitro and in vivo anti-myeloma activity and synergizes with current anti-myeloma agents
BRITISH JOURNAL OF CANCER
2014; 110 (9): 2224-2231
Small molecule MIRA-1 induced mutant p53-dependent apoptosis in several types of solid tumours. However, anti-tumour activity of MIRA-1 in haematological malignancies including multiple myeloma (MM) is unknown. In this study, we evaluated the effect of MIRA-1 in MM.We examined the anti-tumour activity of MIRA-1 alone or in combination with current anti-myeloma agents in a panel of MM cell lines, primary MM samples, and in a mouse xenograft model of MM.MIRA-1 treatment resulted in the inhibition of viability, colony formation, and migration and increase in apoptosis of MM cells irrespective of p53 status accompanied by upregulation of Puma and Bax and downregulation of Mcl-1 and c-Myc. Genetic knockdown of p53 did not abrogate apoptotic response of MIRA-1. MIRA-1 triggered activation of PERK and IRE-α leading to splicing of XBP1 indicating an association of endoplasmic reticulum stress response. Furthermore, combined treatment of MIRA-1 with dexamethasone, doxorubicin or velcade displayed synergistic response in MM cells. Importantly, MIRA-1 alone or in combination with dexamethasone retarded tumour growth and prolonged survival without showing any untoward toxicity in the mice bearing MM tumour.Our data provide the preclinical framework for clinical evaluation of MIRA-1 as a novel therapeutic agent to improve patient outcome in MM.
View details for DOI 10.1038/bjc.2014.164
View details for Web of Science ID 000335562800009
View details for PubMedID 24691427
CD11b expression correlates with monosomal karyotype and predicts an extremely poor prognosis in cytogenetically unfavorable acute myeloid leukemia
2013; 37 (2): 122-128
Several cytogenetic features, including monosomal karyotype (MK), have been associated with unfavorable prognosis in acute myeloid leukemia (AML). However, little is known about the prognostic significance of immunophenotypes in AML patients with unfavorable-risk cytogenetics. We evaluated immunophenotypes, cytogenetics, clinical features and survival outcomes in 233 uniformly treated AML patients who harbored unfavorable cytogenetics. CD11b expression was observed in 145 (70%) of 208 patients and emerged as an independent prognostic factor for inferior overall survival in multivariate analysis (p=0.024). MK and age ? 60 years were predictors for lower complete remission rate (p=0.017, p<0.0001, respectively) and shorter overall survival (p=0.024, p<0.0001), while complex karyotype (CK) predicted a shorter overall survival (p=0.013). CD11b expression was strongly correlated with MK and identified a subset of patients with MK who had extremely poor overall survival. We proposed a prognostic scoring model using CD11b positivity, age ? 60 years, the presence of MK and the presence of CK to classify the patients into distinct risk groups. We identified the poor prognosis of CD11b expression and validated the adverse influence of MK, CK and age ? 60 years in cytogenetically unfavorable AML patients. Our proposed scoring model may be adapted in clinical practice to further the stratification of this high-risk population.
View details for DOI 10.1016/j.leukres.2012.09.019
View details for Web of Science ID 000313636700002
View details for PubMedID 23092917
CD11b expression correlates with monosomal karyotype and predicts an extremely poor prognosis in cytogenetically unfavourable acute myeloid leukemia.
View details for PubMedID 23664038
Cyclin kinase subunit 1B nuclear expression predicts an adverse outcome for patients with relapsed/refractory multiple myeloma treated with bortezomib
2012; 43 (6): 858-864
Amplification of cyclin kinase subunit 1B gene on chromosome 1q21 resulting in overexpression of cyclin kinase subunit 1B has been associated with disease progression in multiple myeloma. Bortezomib is a proteasome inhibitor that induces apoptosis in various cancer cells and has been shown to be effective as a salvage therapy for relapsed/refractory multiple myeloma. Our group has recently reported the adverse effect of 1q21 gains in relapsed and refractory multiple myeloma treated with bortezomib. However, whether nuclear cyclin kinase subunit 1B protein expression correlates with 1q21 gains and has prognostic value in patients with multiple myeloma receiving bortezomib regimen remains unclear. We, therefore, evaluated the nuclear expression of cyclin kinase subunit 1B protein in patients with relapsed/refractory multiple myeloma undergoing bortezomib therapy by immunohistochemistry. The 1q21 amplification status of the same cohort was examined by interphase cytoplasmic immunoglobulin fluorescence in situ hybridization. Of 60 cases, 19 (32%) were positive for cyclin kinase subunit 1B nuclear expression by immunohistochemistry. Seventeen (89%) of the immunohistochemistry-positive cases had 1q21 gain detected by cytoplasmic immunoglobulin fluorescence in situ hybridization, and 17 (77%) of the 22 cases with 1q21 gain showed increased cyclin kinase subunit 1B protein expression. cyclin kinase subunit 1B expression and 1q21 gain were strongly correlated (P < .0001). There was no significant difference in response rate between patients with and without cyclin kinase subunit 1B nuclear expression. However, patients with cyclin kinase subunit 1B expression had a significantly shorter progression-free survival (1.9 versus 5.6 months; P < .0001) and overall survival (4.9 versus 22.4 months; P = .012) compared with those without cyclin kinase subunit 1B expression. Our results indicated that cyclin kinase subunit 1B nuclear expression detected by immunohistochemistry is an adverse prognostic factor for patients with multiple myeloma treated with bortezomib therapy.
View details for DOI 10.1016/j.humpath.2011.07.013
View details for Web of Science ID 000304728200010
View details for PubMedID 22047644
p53 Nuclear Expression Correlates With Hemizygous TP53 Deletion and Predicts an Adverse Outcome for Patients With Relapsed/Refractory Multiple Myeloma Treated With Lenalidomide
AMERICAN JOURNAL OF CLINICAL PATHOLOGY
2012; 137 (2): 208-212
del(17p13)(TP53) seems to be an independent poor prognostic factor in patients with relapsed/refractory multiple myeloma (MM) receiving lenalidomide. However, whether aberrant p53 nuclear expression detected by immunohistochemical analysis can be used as a surrogate marker for del(17p13)(TP53) in prognostic evaluation of lenalidomide-treated relapsed/refractory MM remains unclear. The p53 expression in myeloma cells from 88 patients was evaluated by immunohistochemical analysis, and 17p13(TP53) gene status was examined by fluorescence in situ hybridization (FISH). FISH detected hemizygous del(17p13)(TP53) in 13 (15%), and immunohistochemical analysis detected p53 nuclear expression in 11 cases (13%). del(17p13) (TP53) and p53 expression were strongly correlated (P < .0001). Furthermore, patients with aberrant p53 nuclear expression had significantly shorter progression-free and overall survival than patients without this abnormality. Our results suggest that p53 nuclear expression is associated with adverse outcome in patients with relapsed/refractory MM receiving lenalidomide-based therapy and that p53 immunohistochemical analysis may serve as a simple, rapid method to predict del(17p13)(TP53) in this patient subgroup.
View details for DOI 10.1309/AJCPHC85DGAXZDBE
View details for Web of Science ID 000299484900006
View details for PubMedID 22261445