Role of 1Q21 in Multiple Myeloma: from Pathogenesis to Possible Therapeutic Targets

cells Review Role of 1q21 in Multiple Myeloma: From Pathogenesis to Possible Therapeutic Targets Jessica Burroughs Garcìa 1,2, Rosa Alba Eufemiese 1, Paola Storti 1 , Gabriella Sammarelli 3, Luisa Craviotto 1,3, Giannalisa Todaro 3, Denise Toscani 1, Valentina Marchica 1 and Nicola Giuliani 1,3,* 1 Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; [email protected] (J.B.G.); [email protected] (R.A.E.); [email protected] (P.S.); [email protected] (L.C.); [email protected] (D.T.); [email protected] (V.M.) 2 Department of Medical-Veterinary Science, University of Parma, 43121 Parma, Italy 3 Hematology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; [email protected] (G.S.); [email protected] (G.T.) * Correspondence: [email protected] Abstract: Multiple myeloma (MM) is characterized by an accumulation of malignant plasma cells (PCs) in the bone marrow (BM). The amplification of 1q21 is one of the most common cytogenetic abnormalities occurring in around 40% of de novo patients and 70% of relapsed/refractory MM. Patients with this unfavorable cytogenetic abnormality are considered to be high risk with a poor response to standard therapies. The gene(s) driving amplification of the 1q21 amplicon has not been fully studied. A number of clear candidates are under investigation, and some of them (IL6R, ILF2, MCL-1, CKS1B and BCL9) have been recently proposed to be potential drivers of this region. However, much remains to be learned about the biology of the genes driving the disease progression in MM patients with 1q21 amp. Understanding the mechanisms of these genes is important for the Citation: Burroughs Garcìa, J.; development of effective targeted therapeutic approaches to treat these patients for whom effective Eufemiese, R.A.; Storti, P.; Sammarelli, G.; Craviotto, L.; Todaro, G.; Toscani, therapies are currently lacking. In this paper, we review the current knowledge about the pathological D.; Marchica, V.; Giuliani, N. Role of features, the mechanism of 1q21 amplification, and the signal pathway of the most relevant candidate 1q21 in Multiple Myeloma: From genes that have been suggested as possible therapeutic targets for the 1q21 amplicon. Pathogenesis to Possible Therapeutic Targets. Cells 2021, 10, 1360. https:// Keywords: multiple myeloma; 1q21; chromosome aberrations; amplification; IL6R; ILF2; MCL-1; doi.org/10.3390/cells10061360 CKS1B; BCL9 Academic Editor: Marco Rossi Received: 11 May 2021 1. Introduction Accepted: 28 May 2021 Multiple myeloma (MM) is characterized by an abnormal proliferation of plasma Published: 1 June 2021 cells (PCs) in the bone marrow (BM). Despite the significant improvement in overall survival (OS), most MM patients eventually relapse and develop refractory disease [1]. Publisher’s Note: MDPI stays neutral MM is a genetically complex disease characterized by a distinct clinical heterogeneity in with regard to jurisdictional claims in the response rate and survival outcomes. Nevertheless, the progression of the disease published maps and institutional affil- demonstrates a wide range of heterogeneity, with the OS time ranging from less than iations. 12 months to more than 10 years [2,3]. The heterogeneity in MM can be explained either by the intrinsic genetic heterogeneity of PCs or at least in part by the BM microenvironment, which generates a high-risk environment that facilitates cancer cell survival [4–6]. The presence or absence of recurrent chromosomal abnormalities is considered one Copyright: © 2021 by the authors. of the major prognostic landmarks for MM patients. Primary immunoglobulin translo- Licensee MDPI, Basel, Switzerland. cations (t) involving immunoglobulin heavy chain (IGH) at the 14q32 region including This article is an open access article t(4;14), t(14;16), t(14;20), and the hyperdiploid including trisomies of the odd-numbered distributed under the terms and chromosomes, occur as initiating events during tumor pathogenesis (Figure1) . Secondary conditions of the Creative Commons abnormalities occur later during disease progression. The most frequent secondary ab- Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ normalities can be classified as translocations, mutations, deletions, and amplifications 4.0/). (Figure1) . MYC translocation is found in about 15% of MM at diagnosis and 50% of more Cells 2021, 10, 1360. https://doi.org/10.3390/cells10061360 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 15 Cells 2021, 10, 1360 2 of 14 malities can be classified as translocations, mutations, deletions, and amplifications (Fig- ure 1). MYC translocation is found in about 15% of MM at diagnosis and 50% of more advancedadvanced stages stages [ 7[7].]. Approximately Approximately one-third one-third of ofMYC MYCtranslocations translocations involve involve rearrange- rearrange- mentsments with with the theIGH IGHlocus locus [8,9 [8,9].]. In addition, In addition, copy copy number number change change at the MYCat thelocus MYC is locus found is infound around in 20%around of NDMM20% of NDMM patients patients [9]. The overexpression[9]. The overexpression of MYC isof typicallyMYC is typically associated as- withsociated a poor with prognosis a poor inprognosis patients within patients MM. The withRAS MM.gene The family RAS ( NRASgene familyand KRAS (NRAS) is one and ofKRAS the most) is one frequently of the most mutated frequently groups mutated of genes groups in MM of [10 genes]. The in prevalence MM [10]. The of both prevalenceNRAS andof bothKRAS NRASmutations and KRAS in MM mutations patients in is betweenMM patients 20 and is between 35%. It has 20 beenand 35%. suggested It has thatbeen KRASsuggestedplays that a more KRAS influential plays a more role in influential the pathogenesis role in the of MM.pathogenesisRAS mutations of MM. are RAS usually muta- associatedtions are usually with less associated favorable with disease less favo outcomes,rable disease greater outcomes, tumor burden, greater and tumor shortened burden, survivaland shortened time [10 survival]. The tumor time [10]. suppressor The tumor gene suppressorTP53 is located gene TP53 on chromosome is located on 17 chromo- (17p). Deletionssome 17 (17p). of the Deletions 17p region of can the lead17p toregion monoallelic can lead inactivation to monoallelic of TP53 inactivation[11]. Recently, of TP53 bi-allelic[11]. Recently, inactivation bi-allelic of TP53 inactivationhas been of associated TP53 has with been high associated risk, poor with OS, high and risk, resistance poor OS, to conventionaland resistance MM to treatmentsconventional [12 ,13MM]. Intreatments MM, TP53 [12,13].mutations In MM, are uncommon TP53 mutations at diagnosis are un- andcommon represent at diagnosis late events and in diseaserepresent progression, late events suggested in disease to progression, play an essential suggested role in to MM play pathogenesisan essential role [13,14 in]. MM In a pathogenesis multivariate analysis,[13,14]. In D’Agostino a multivariate et al. analysis, showed thatD’Agostino mutation et of al. P53showedwas correlated that mutation with of early P53 relapse was correlated in MM patients. with early In addition,relapse in the MM study patients. showed In addi- that patientstion, the with study both, showed deletion that of patients the 17p with and P53both,mutations, deletion of have the a17p shorter and OSP53 comparedmutations, tohave patients a shorter with OS only compared one chromosomal to patients aberrationwith only one [15]. chromosomal An increased aberration risk of acquired [15]. An P53increasedmutation risk was of acquired also observed P53 mutation in patients was carrying also observed a deletion in patients of 17p carrying [15]. Along a deletion with TP53of 17pmutation, [15]. Along deletion with ofTP53 chromosome mutation,13 deletion has also of been chromosome associated 13 with has adversealso been disease associ- outcomeated with [16 adverse]. disease outcome [16]. FigureFigure 1. 1.Genetic Genetic events events from from initiation initiation to progressionto progression in multiple in multiple myeloma myeloma pathogenesis. pathogenesis. Chromosomal Chromosomal aberrations aberrations involv- in- ingvolving immunoglobulin immunoglobulin heavy heavy chain (chainIGH) at(IGH) the 14q32at the region14q32 andregion the and hyperdiploid the hyperdiplo are consideredid are considered primary primary translocations transloca- as theytions are as mutually they are exclusive mutually and exclusive present and in asymptomatic present in asymptomatic stages. Secondary stages. aberrations Secondary follow aberrations primary follow events primary contributing events tocontributing tumor progression to tumor and progression relapse. Secondary and relapse. events Secondary cooperate events with primarycooperate events with toprimary produce events the malignant to produce PC the phenotype. malignant ThePC progression phenotype. from The MGUS-SMMprogression from to MM MGUS-SMM is associated to with MM RAS is associated mutation, MYCwith overexpression,RAS mutation, andMYC amplification overexpression, of 1q21. and Incidenceamplification of MYC of 1q21. translocation, Incidence deletion of MYC of translocation, 17p, and recurrent deletion mutations of 17p, and increased recurrent as disease mutations progressed. increased The as initiation disease pro- of gressed. The initiation of aberrant clones at the onset of the disease is indicated in yellow. Red indicates the

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