Advances in the pathogenesis and diagnosis of multiple myeloma
Summary Multiple myeloma (MM) is a tumor of indolent, bone marrow (BM) localized, isotype‐switched plasma cells. Recently, the diagnostic criteria have been amended to include some patients who would previously have been diagnosed with ultra‐high‐risk smoldering MM and benefit from immediate treatme...
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| Published in | International journal of laboratory hematology Vol. 37; no. S1; pp. 108 - 114 |
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| Main Authors | , |
| Format | Journal Article |
| Language | English |
| Published |
England
Blackwell Publishing Ltd
01.05.2015
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Summary
Multiple myeloma (MM) is a tumor of indolent, bone marrow (BM) localized, isotype‐switched plasma cells. Recently, the diagnostic criteria have been amended to include some patients who would previously have been diagnosed with ultra‐high‐risk smoldering MM and benefit from immediate treatment. Genetically it can be divided into tumors with different recurrent immunoglobulin heavy chain gene translocations (4p16, 11q13, 6p21, 16q23, 20q11) and tumors characterized by hyperdiploidy with multiple trisomies. Recent genomic studies have shown that almost half of untreated patients have a genetic rearrangements of the MYC locus that result in juxtaposition of ectopic super‐enhancers adjacent to MYC, as well as somatic mutations that activate the RAS/MAPK pathway (NRAS, KRAS, BRAF, FGFR3). Mutations that result in constitutive activation of the NFkB pathway and that inactivate TP53, CDKN2C, KDM6A, FAM46C, and DIS3 are also recurrent. A major insight from these studies has been the recognition of the high degree of subclonal heterogeneity in MM, which is more frequent in patients with high‐risk genetics. The subclones may alternate in dominance under alternating therapeutic pressure, a phenomenon known as ‘clonal tides’. The identification of marked subclonal heterogeneity argues in those patients for the use of therapeutic strategies to maximize response, and long‐term suppressive therapies to prevent tumor regrowth and development of additional subclones. |
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| AbstractList | Multiple myeloma (MM) is a tumor of indolent, bone marrow (BM) localized, isotype-switched plasma cells. Recently, the diagnostic criteria have been amended to include some patients who would previously have been diagnosed with ultra-high-risk smoldering MM and benefit from immediate treatment. Genetically it can be divided into tumors with different recurrent immunoglobulin heavy chain gene translocations (4p16, 11q13, 6p21, 16q23, 20q11) and tumors characterized by hyperdiploidy with multiple trisomies. Recent genomic studies have shown that almost half of untreated patients have a genetic rearrangements of the MYC locus that result in juxtaposition of ectopic super-enhancers adjacent to MYC, as well as somatic mutations that activate the RAS/MAPK pathway (NRAS, KRAS, BRAF, FGFR3). Mutations that result in constitutive activation of the NFkB pathway and that inactivate TP53, CDKN2C, KDM6A, FAM46C, and DIS3 are also recurrent. A major insight from these studies has been the recognition of the high degree of subclonal heterogeneity in MM, which is more frequent in patients with high-risk genetics. The subclones may alternate in dominance under alternating therapeutic pressure, a phenomenon known as 'clonal tides'. The identification of marked subclonal heterogeneity argues in those patients for the use of therapeutic strategies to maximize response, and long-term suppressive therapies to prevent tumor regrowth and development of additional subclones. Summary Multiple myeloma ( MM ) is a tumor of indolent, bone marrow (BM) localized, isotype‐switched plasma cells. Recently, the diagnostic criteria have been amended to include some patients who would previously have been diagnosed with ultra‐high‐risk smoldering MM and benefit from immediate treatment. Genetically it can be divided into tumors with different recurrent immunoglobulin heavy chain gene translocations (4p16, 11q13, 6p21, 16q23, 20q11) and tumors characterized by hyperdiploidy with multiple trisomies. Recent genomic studies have shown that almost half of untreated patients have a genetic rearrangements of the MYC locus that result in juxtaposition of ectopic super‐enhancers adjacent to MYC, as well as somatic mutations that activate the RAS/MAPK pathway (NRAS, KRAS, BRAF, FGFR3). Mutations that result in constitutive activation of the NFkB pathway and that inactivate TP53, CDKN2C, KDM6A, FAM46C, and DIS3 are also recurrent. A major insight from these studies has been the recognition of the high degree of subclonal heterogeneity in MM , which is more frequent in patients with high‐risk genetics. The subclones may alternate in dominance under alternating therapeutic pressure, a phenomenon known as ‘clonal tides’. The identification of marked subclonal heterogeneity argues in those patients for the use of therapeutic strategies to maximize response, and long‐term suppressive therapies to prevent tumor regrowth and development of additional subclones. Summary Multiple myeloma (MM) is a tumor of indolent, bone marrow (BM) localized, isotype‐switched plasma cells. Recently, the diagnostic criteria have been amended to include some patients who would previously have been diagnosed with ultra‐high‐risk smoldering MM and benefit from immediate treatment. Genetically it can be divided into tumors with different recurrent immunoglobulin heavy chain gene translocations (4p16, 11q13, 6p21, 16q23, 20q11) and tumors characterized by hyperdiploidy with multiple trisomies. Recent genomic studies have shown that almost half of untreated patients have a genetic rearrangements of the MYC locus that result in juxtaposition of ectopic super‐enhancers adjacent to MYC, as well as somatic mutations that activate the RAS/MAPK pathway (NRAS, KRAS, BRAF, FGFR3). Mutations that result in constitutive activation of the NFkB pathway and that inactivate TP53, CDKN2C, KDM6A, FAM46C, and DIS3 are also recurrent. A major insight from these studies has been the recognition of the high degree of subclonal heterogeneity in MM, which is more frequent in patients with high‐risk genetics. The subclones may alternate in dominance under alternating therapeutic pressure, a phenomenon known as ‘clonal tides’. The identification of marked subclonal heterogeneity argues in those patients for the use of therapeutic strategies to maximize response, and long‐term suppressive therapies to prevent tumor regrowth and development of additional subclones. |
| Author | Chesi, M. Bergsagel, P. L. |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25976968$$D View this record in MEDLINE/PubMed |
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Blood 2012;120:376-85. 2009; 23 2012; 120 2011; 146 2014; 5 2012; 122 2011; 117 2013; 88 2005; 106 2010; 375 2014; 15 2014; 25 2008; 13 2009; 113 2013; 121 2014; 28 2011; 25 2011; 17 2011; 471 2011; 470 2007; 12 2012; 30 2014; 64 e_1_2_11_10_1 e_1_2_11_14_1 e_1_2_11_13_1 e_1_2_11_12_1 e_1_2_11_11_1 e_1_2_11_7_1 e_1_2_11_6_1 e_1_2_11_5_1 e_1_2_11_4_1 e_1_2_11_26_1 e_1_2_11_3_1 e_1_2_11_2_1 e_1_2_11_21_1 e_1_2_11_20_1 e_1_2_11_25_1 e_1_2_11_24_1 e_1_2_11_9_1 e_1_2_11_23_1 e_1_2_11_8_1 e_1_2_11_22_1 e_1_2_11_18_1 e_1_2_11_17_1 e_1_2_11_16_1 e_1_2_11_15_1 e_1_2_11_19_1 |
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Multiple myeloma (MM) is a tumor of indolent, bone marrow (BM) localized, isotype‐switched plasma cells. Recently, the diagnostic criteria have been... Multiple myeloma (MM) is a tumor of indolent, bone marrow (BM) localized, isotype-switched plasma cells. Recently, the diagnostic criteria have been amended to... Summary Multiple myeloma ( MM ) is a tumor of indolent, bone marrow (BM) localized, isotype‐switched plasma cells. Recently, the diagnostic criteria have been... |
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| SubjectTerms | Gene Rearrangement Humans Models, Genetic Multiple Myeloma - diagnosis Multiple Myeloma - genetics Mutation Myeloma Proto-Oncogene Proteins c-myc - genetics Signal Transduction - genetics Translocation, Genetic Trisomy |
| Title | Advances in the pathogenesis and diagnosis of multiple myeloma |
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