Abstract
Multiple myeloma (MM) is an incurable haematological malignancy characterised by the proliferation of mature antibody-secreting plasma B cells in the bone marrow. MM can arise from initiating translocations, of which the musculoaponeurotic fibrosarcoma (MAF) family is implicated in ∼5%. MMs bearing Maf translocations are of poor prognosis. These translocations are associated with elevated Maf expression, including c-MAF, MAFB and MAFA, and with t(14;16) and t(14;20) translocations, involving c-MAF and MAFB, respectively. c-MAF is also overexpressed in MM through MEK/ERK activation, bringing the number of MMs driven by the deregulation of a Maf gene close to 50%. Here we demonstrate that MAFB and c-MAF are phosphorylated by the Ser/Thr kinase GSK3 in human MM cell lines. We show that LiCl-induced GSK3 inhibition targets these phosphorylations and specifically decreases proliferation and colony formation of Maf-expressing MM cell lines. Interestingly, bortezomib induced stabilisation of Maf phosphorylation, an observation that could explain, at least partially, the low efficacy of bortezomib for patients carrying Maf translocations. Thus, GSK3 inhibition could represent a new therapeutic approach for these patients.
Highlights
Multiple myeloma (MM) is an incurable B-cell neoplasm of the bone marrow with a complex array of clinical manifestations.[1,2,3,4,5]MM is further divided into seven disease subtypes based on molecular heterogeneity.[6,7] Of these, one subtype corresponds to the recurrent translocations t(14;16) and t(14;20) involving different musculoaponeurotic fibrosarcoma (Maf) genes juxtaposed to immunoglobulin heavy chain enhancer elements, leading to their aberrant overexpression
We previously demonstrated that MAFA is sequentially phosphorylated on residues Serine 61 (S61), Threonine 57, 53, 49 (T57, T53 and S49) by GSK3.17 These putative GSK3 phosphorylation sites are highly conserved amongst the large Maf proteins; MAFB and c-musculoaponeurotic fibrosarcoma (MAF) (Figure 1a)
To investigate whether MAFB and c-MAF are phosphorylated by GSK3 on the corresponding residues, we generated constructs expressing the wild type (WT) phosphorylatable forms and the mutant unphosphorylatable forms (4A) where the four putative GSK3 phosphorylation sites were mutated into alanine (Figure 1a)
Summary
MM is further divided into seven disease subtypes based on molecular heterogeneity.[6,7] Of these, one subtype corresponds to the recurrent translocations t(14;16) and t(14;20) involving different musculoaponeurotic fibrosarcoma (Maf) genes juxtaposed to immunoglobulin heavy chain enhancer elements, leading to their aberrant overexpression. Maf oncoproteins are basic leucine zipper transcription factors belonging to the AP-1 super family.[13] The Maf family is composed of seven members that can be classified into two subfamilies, the large and small Maf genes. The large Maf members, MAFA, MAFB, c-MAF and NRL, differ from the small Maf members (MAFF, MAFG and MAFK) by the presence of a transactivation domain in their amino terminus.[13] We and others demonstrated that large Maf proteins display strong transforming activity in chicken embryo fibroblasts, with MAFA being the most potent oncoprotein.[14,15,16]
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