Leukemia & Lymphoma, March 2015; 56(3): 551–552 ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.961015
COMMENTARY
Appraising myc involvement in high risk myeloma Efstathios Kastritis & Meletios A. Dimopoulos Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece Multiple myeloma (MM) is characterized by significant heterogeneity in terms of presentation of the disease and eventual patient outcome. This heterogeneity is linked to the pathobiology of the malignant plasma cell clone. According to current knowledge of the biology of this malignancy, a period of slowly proliferative disease, monoclonal gammopathy of undetermined significance (MGUS), precedes the development of symptomatic myeloma, for a few or several years. The transition from MGUS to asymptomatic and then symptomatic myeloma is the result of accumulation of genetic alterations in inherently genetically unstable tumor cells [1]. Several genetic alterations have been implicated in the pathogenesis of MM, with n two main pathways involving either hyperdiploidy or specific translocations of the immunoglobulin heavy chain (IgH) loci in chromosome 14 [2]. It has been recognized that alterations of chromosome 8 involving the c-myc locus constitute an additional event that is associated with a more aggressive transformation of MM. However, this is considered a late event, occurring in patients with very advanced disease, and is commonly encountered in human myeloma cell lines. Other genetic changes such as loss of 17p are also associated with a more aggressive course and short remission duration. Thus, the presence of genetic abnormalities such as t(4;14) and del17p are associated with poor survival, while others such as t(11;14) have a neutral prognostic effect. Hyperdiploidy is associated with a more favorable outcome compared with non-hyperdiploid karyotypes. Additional cytogenetic abnormalities such as add1q21, del1p, t(14;16) and t(14;20) have also been implicated as high risk markers, but their independent impact has not yet been established [3]. Until recently, and despite the fact that overexpression of myc is associated with a more aggressive phenotype, the presence of myc alterations was not routinely assessed in newly diagnosed patients, and their prognostic significance has not been studied in MM. However, recent evidence indicates that c-myc overexpression may be an earlier and more frequent event in newly diagnosed patients with MM than initially believed. Walker et al. used DNA capture and an extensive parallel sequencing approach in 104
newly diagnosed patients with myeloma and identified 8q24 breakpoints in 21 (20%) of these samples, with partner loci including IGH, IGK and IGL, XBP1, FAM46C, CCND1 and KRAS. These translocations were associated with increased expression of MYC, and decreased progression-free and overall survival [4]. Affer et al. identified MYC rearrangements in close to 50% of cases of MM, including smoldering MM. These rearrangements repositioned MYC near a limited number of genes associated with conventional enhancers, but mostly with super-enhancers (e.g. IGH, IGL, IGK, NSMCE2, TXNDC5, FAM46C, FOXO3, IGJ, PRDM1), and were associated with a significant increase of monoallelic MYC expression. Furthermore, MM tumors lacking a rearrangement had biallelic MYC expression at significantly higher levels than in MGUS [5]. Both of the above studies used advanced technology which is not widely available. In this issue of the journal, Glitza et al. [6] retrospectively investigated the presence of myc alterations that were identified with conventional karyotype and standard fluorescence in situ hybridization (FISH). Their data indicate that c-myc related abnormalities are associated with a fairly poor outcome in patients with MM, and the disease in these patients presented with an aggressive phenotype: 52% of patients bearing myc abnormalities presented with plasma cell leukemia (PCL) or extramedullary involvement. Although myc overexpression is generally linked to late and advanced stages of the disease, it seems that in some patients abnormalities of chromosome 8 may occur earlier, resulting in an aggressive transformation. Typically, in most patients, chromosome 8 rearrangements included translocations to either chromosome 14q, which harbors IgH genes, or chromosome 22, which harbors IgL genes. Notably, despite therapy with novel agents and the use of intensive regimens, the outcome of patients bearing myc abnormalities was still quite dismal, with a median survival of only 20 months. This was due to a very short duration of response (median 9.5 months), despite the non-inferior response rates (in the range of 75–80%). Thus, the report by Glitza et al. provides further evidence for the fact that cytogenetic abnormalities involving the c-myc locus are a marker of high risk disease with poor outcome,
Correspondence: Dr. Meletios A. Dimopoulos, MD, Department of Clinical Therapeutics, “Alexandra” Hospital, 80 Vas. Sofias Ave., 115 28 Athens, Greece. Tel: ⫹ 30-210-338-1541. Fax: ⫹ 30-213-216-2511. E-mail: [email protected] © 2015 Informa UK Ltd. This is an open-access article distributed under the terms of the CC-BY-NC-ND 3.0 License which permits users to download and share the article for non-commercial purposes, so long as the article is reproduced in the whole without changes, and provided the original source is credited. This commentary accompanies an article to be published in Leukemia & Lymphoma. Please refer to the table of contents of the print issue in which this commentary appears.
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similar to that seen in patients with concurrent International Staging System (ISS)-3 stage, the presence of del17p or t(4;14) and elevated lactate dehydrogenase (LDH) levels [7]. Hence, in the light of all the above data, should testing for myc rearrangements be recommended in all newly diagnosed patients with MM, as a part of the standard cytogenetics panel, along with del17p and t(4;14)? As the authors recognize and point out, the incidence of myc rearrangements is probably underestimated, because in most cases testing for myc was not routinely performed. Furthermore, testing for myc was probably performed only in patients with highly proliferative tumors and a very aggressive clinical course; this is depicted by the fact that a conventional karyotype was used for the initial recognition of chromosome 8 abnormalities, while most patients with myeloma have uninformative metaphase karyotypes due to slowly proliferating tumors. Thus, there may well have been a selection of patients with aggressive, poor risk disease in which myc abnormalities were more readily identified. In this respect the impact of other cytogenetic abnormalities known to be associated with poor outcomes, such as del17p, should also be considered, although only two patients in the current study had del17p while five had del13q with conventional karyotyping, but no data on relevant FISH studies are described. Investigation of c-myc rearrangements using FISH is commonly performed in other malignancies such as Burkitt lymphoma, and is widely available. Evaluation of myc rearrangements should be further investigated not only for better clarification of its prognostic significance but also because of the possible opportunity of targeted treatments. myc is a key regulator of the expression of many genes, and down-regulation of its expression may be a promising treatment approach for some patients with myeloma. It has been postulated that MM cells, even at early stages of the disease, may be addicted to myc overexpression, and this myc-addiction could perhaps be exploited to kill MM cells [8,9]. Recent reports indicate that drugs such as BET (bromodomain and extra-terminal) inhibitors, which modulate c-myc expression, may well have activity in MM [10,11]
and are currently under investigation in phase I studies in a number of hematologic malignancies, including MM. An approach based on myc overexpression could be used as a biomarker to select patients with a potentially higher probability of responding to anti-myc therapy. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Palumbo A , Anderson K. Multiple myeloma. N Engl J Med 2011; 364:1046–1060. [2] Bergsagel PL, Kuehl WM. Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol 2005;23:6333–6338. [3] Fonseca R, Bergsagel PL, Drach J, et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia 2009;23:2210–2221. [4] Walker BA , Wardell CP, Brioli A , et al. Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients. Blood Cancer J 2014;4:e191. [5] Affer M, Chesi M, Chen WD, et al. Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma. Leukemia 2014; 28:1725–1735. [6] Glitza IC, Lu G, Shah R, et al. Chromosome 8q24.1/c-MYC abnormality: a marker for high-risk myeloma. Leuk Lymphoma 2015;56:602–607. [7] Moreau P, Planche L, Attal M, et al. The combination of ISS 3, high LDH and t(4;14) and/or del(17p) identify a simple prognostic index for overall survival in patients treated with novel agents-based induction therapy and front-line autologous stem cell transplantation, and allow the definition of a subgroup of patients at high-risk of early death from progressive disease. Blood 2012;120(Suppl. 1) Abstract 598. [8] Holien T, Vatsveen TK, Hella H, et al. Addiction to c-MYC in multiple myeloma. Blood 2012;120:2450–2453. [9] Kuehl WM, Bergsagel PL. MYC addiction: a potential therapeutic target in MM. Blood 2012;120:2351–2352. [10] Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 2011;146: 904–917. [11] Chaidos A , Caputo V, Gouvedenou K, et al. Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood 2014;123:697–705.
Copyright of Leukemia & Lymphoma is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
COMMENTARY
Appraising myc involvement in high risk myeloma Efstathios Kastritis & Meletios A. Dimopoulos Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece Multiple myeloma (MM) is characterized by significant heterogeneity in terms of presentation of the disease and eventual patient outcome. This heterogeneity is linked to the pathobiology of the malignant plasma cell clone. According to current knowledge of the biology of this malignancy, a period of slowly proliferative disease, monoclonal gammopathy of undetermined significance (MGUS), precedes the development of symptomatic myeloma, for a few or several years. The transition from MGUS to asymptomatic and then symptomatic myeloma is the result of accumulation of genetic alterations in inherently genetically unstable tumor cells [1]. Several genetic alterations have been implicated in the pathogenesis of MM, with n two main pathways involving either hyperdiploidy or specific translocations of the immunoglobulin heavy chain (IgH) loci in chromosome 14 [2]. It has been recognized that alterations of chromosome 8 involving the c-myc locus constitute an additional event that is associated with a more aggressive transformation of MM. However, this is considered a late event, occurring in patients with very advanced disease, and is commonly encountered in human myeloma cell lines. Other genetic changes such as loss of 17p are also associated with a more aggressive course and short remission duration. Thus, the presence of genetic abnormalities such as t(4;14) and del17p are associated with poor survival, while others such as t(11;14) have a neutral prognostic effect. Hyperdiploidy is associated with a more favorable outcome compared with non-hyperdiploid karyotypes. Additional cytogenetic abnormalities such as add1q21, del1p, t(14;16) and t(14;20) have also been implicated as high risk markers, but their independent impact has not yet been established [3]. Until recently, and despite the fact that overexpression of myc is associated with a more aggressive phenotype, the presence of myc alterations was not routinely assessed in newly diagnosed patients, and their prognostic significance has not been studied in MM. However, recent evidence indicates that c-myc overexpression may be an earlier and more frequent event in newly diagnosed patients with MM than initially believed. Walker et al. used DNA capture and an extensive parallel sequencing approach in 104
newly diagnosed patients with myeloma and identified 8q24 breakpoints in 21 (20%) of these samples, with partner loci including IGH, IGK and IGL, XBP1, FAM46C, CCND1 and KRAS. These translocations were associated with increased expression of MYC, and decreased progression-free and overall survival [4]. Affer et al. identified MYC rearrangements in close to 50% of cases of MM, including smoldering MM. These rearrangements repositioned MYC near a limited number of genes associated with conventional enhancers, but mostly with super-enhancers (e.g. IGH, IGL, IGK, NSMCE2, TXNDC5, FAM46C, FOXO3, IGJ, PRDM1), and were associated with a significant increase of monoallelic MYC expression. Furthermore, MM tumors lacking a rearrangement had biallelic MYC expression at significantly higher levels than in MGUS [5]. Both of the above studies used advanced technology which is not widely available. In this issue of the journal, Glitza et al. [6] retrospectively investigated the presence of myc alterations that were identified with conventional karyotype and standard fluorescence in situ hybridization (FISH). Their data indicate that c-myc related abnormalities are associated with a fairly poor outcome in patients with MM, and the disease in these patients presented with an aggressive phenotype: 52% of patients bearing myc abnormalities presented with plasma cell leukemia (PCL) or extramedullary involvement. Although myc overexpression is generally linked to late and advanced stages of the disease, it seems that in some patients abnormalities of chromosome 8 may occur earlier, resulting in an aggressive transformation. Typically, in most patients, chromosome 8 rearrangements included translocations to either chromosome 14q, which harbors IgH genes, or chromosome 22, which harbors IgL genes. Notably, despite therapy with novel agents and the use of intensive regimens, the outcome of patients bearing myc abnormalities was still quite dismal, with a median survival of only 20 months. This was due to a very short duration of response (median 9.5 months), despite the non-inferior response rates (in the range of 75–80%). Thus, the report by Glitza et al. provides further evidence for the fact that cytogenetic abnormalities involving the c-myc locus are a marker of high risk disease with poor outcome,
Correspondence: Dr. Meletios A. Dimopoulos, MD, Department of Clinical Therapeutics, “Alexandra” Hospital, 80 Vas. Sofias Ave., 115 28 Athens, Greece. Tel: ⫹ 30-210-338-1541. Fax: ⫹ 30-213-216-2511. E-mail: [email protected] © 2015 Informa UK Ltd. This is an open-access article distributed under the terms of the CC-BY-NC-ND 3.0 License which permits users to download and share the article for non-commercial purposes, so long as the article is reproduced in the whole without changes, and provided the original source is credited. This commentary accompanies an article to be published in Leukemia & Lymphoma. Please refer to the table of contents of the print issue in which this commentary appears.
551
552
E. Kastritis & M. A. Dimopoulos
similar to that seen in patients with concurrent International Staging System (ISS)-3 stage, the presence of del17p or t(4;14) and elevated lactate dehydrogenase (LDH) levels [7]. Hence, in the light of all the above data, should testing for myc rearrangements be recommended in all newly diagnosed patients with MM, as a part of the standard cytogenetics panel, along with del17p and t(4;14)? As the authors recognize and point out, the incidence of myc rearrangements is probably underestimated, because in most cases testing for myc was not routinely performed. Furthermore, testing for myc was probably performed only in patients with highly proliferative tumors and a very aggressive clinical course; this is depicted by the fact that a conventional karyotype was used for the initial recognition of chromosome 8 abnormalities, while most patients with myeloma have uninformative metaphase karyotypes due to slowly proliferating tumors. Thus, there may well have been a selection of patients with aggressive, poor risk disease in which myc abnormalities were more readily identified. In this respect the impact of other cytogenetic abnormalities known to be associated with poor outcomes, such as del17p, should also be considered, although only two patients in the current study had del17p while five had del13q with conventional karyotyping, but no data on relevant FISH studies are described. Investigation of c-myc rearrangements using FISH is commonly performed in other malignancies such as Burkitt lymphoma, and is widely available. Evaluation of myc rearrangements should be further investigated not only for better clarification of its prognostic significance but also because of the possible opportunity of targeted treatments. myc is a key regulator of the expression of many genes, and down-regulation of its expression may be a promising treatment approach for some patients with myeloma. It has been postulated that MM cells, even at early stages of the disease, may be addicted to myc overexpression, and this myc-addiction could perhaps be exploited to kill MM cells [8,9]. Recent reports indicate that drugs such as BET (bromodomain and extra-terminal) inhibitors, which modulate c-myc expression, may well have activity in MM [10,11]
and are currently under investigation in phase I studies in a number of hematologic malignancies, including MM. An approach based on myc overexpression could be used as a biomarker to select patients with a potentially higher probability of responding to anti-myc therapy. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Palumbo A , Anderson K. Multiple myeloma. N Engl J Med 2011; 364:1046–1060. [2] Bergsagel PL, Kuehl WM. Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol 2005;23:6333–6338. [3] Fonseca R, Bergsagel PL, Drach J, et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia 2009;23:2210–2221. [4] Walker BA , Wardell CP, Brioli A , et al. Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients. Blood Cancer J 2014;4:e191. [5] Affer M, Chesi M, Chen WD, et al. Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma. Leukemia 2014; 28:1725–1735. [6] Glitza IC, Lu G, Shah R, et al. Chromosome 8q24.1/c-MYC abnormality: a marker for high-risk myeloma. Leuk Lymphoma 2015;56:602–607. [7] Moreau P, Planche L, Attal M, et al. The combination of ISS 3, high LDH and t(4;14) and/or del(17p) identify a simple prognostic index for overall survival in patients treated with novel agents-based induction therapy and front-line autologous stem cell transplantation, and allow the definition of a subgroup of patients at high-risk of early death from progressive disease. Blood 2012;120(Suppl. 1) Abstract 598. [8] Holien T, Vatsveen TK, Hella H, et al. Addiction to c-MYC in multiple myeloma. Blood 2012;120:2450–2453. [9] Kuehl WM, Bergsagel PL. MYC addiction: a potential therapeutic target in MM. Blood 2012;120:2351–2352. [10] Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 2011;146: 904–917. [11] Chaidos A , Caputo V, Gouvedenou K, et al. Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood 2014;123:697–705.
Copyright of Leukemia & Lymphoma is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
