Multiple myeloma pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2] Shyam Patel [3]
Overview
Multiple myeloma arises from post-germinal center plasma cells that are normally involved in production of human immunoglobulins.[1][2][3] Both sporadic events and familial contributions contribute to the pathogenesis of multiple myeloma. Renal involvement by multiple myeloma is catergorized into three entities: light chain cast nephropathy, monoclonal immunoglobulin deposition disease, and amyloidosis. Osseous involvement by multiple myeloma is based on cytokine and cellular interactions that lead to bone breakdown. On microscopic histopathological analysis, abundant eosinophilic cytoplasm, eccentrically placed nucleus, and Russell bodies are characteristic findings of multiple myeloma.[4]
Pathophysiology
Normal physiology and development of plasma cells
- Plasma cells are terminally differentiated B-cells which function to produce immunoglobulins. plasma cells arise from B lymphocytes through a series of events. These events take place in bone marrow and secondary lymphoid tissues.
- These events include immunoglobulin heavy-chain (IgH) VDJ gene rearrangement, migration into lymphoid tissues, somatic hypermutation (SMH) in the IgH and light-chain genes, antigen selection, switch in Ig class from IgM to IgG, IgA, IgD, or IgE, migration back to bone marrow and terminal differentiation into plasma cells.[5] [6][7]
Stem cells → Pre-B cells → Immature B-cells → Mature B-cells (naïve) → Activated B-cells → Memory B-cells and Plasmablasts → Plasma cells
- During these events, B cells express variety of surface markers which may be used to denote their developmental stage such as CD19, CD20, CD27, CD38, CD10, CD138. These markers and IgH chain gene sequences are important to define the nature of myeloma cells.[5][6][7]
- Plasma cells secrete antibodies which function in humoral immunity.[5][6] [7]
- Plasma cells are typically polyclonal and can respond to a variety of antigens, which helps combat infections. Under normal circumstances, there is no monoclonality amongst the plasma cell population in a person. These plasma cells are functionally intact in their ability to contribute to humoral immunity.[5][6][7]
- Transcription factors such as interferon regulatory factor 4 (IRF4), BCL6, B-lymphocyte-induced maturation protein 1 (BLIMP1, also known as PRDM1), paired box gene 5 (PAX5) and X box binding protein 1 (XBP1) play an important role in differentiation and survival of plasma cells.[8][9][10]
Interferon regulatory factor 4 (IRF4) → Down-regulation of BCL6 → Up-regulation of B-lymphocyte-induced maturation protein 1 (BLIMP1) → Down-regulation of paired box gene 5 (PAX5) and Up-regulation of X box binding protein 1 (XBP1).[11][12][13]
For more information on plasma cells, click here.
Normal physiology and development of Immunoglobulins
- Immunoglobulins (also known as Antibodies) are proteins that are found in blood or other bodily fluids of vertebrates, and are used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses.
- They are made of a few basic structural units called chains; each antibody has two large heavy chains H and two small light chains L. There are several different types of antibody heavy chains, and several different kinds of antibodies, which are grouped into different isotypes based on which heavy chain they possess.[14][15]
- Five different antibody isotypes are known in mammals, which perform different roles, and help direct the appropriate immune response for each different type of foreign object they encounter.[14][15]
- Class switch recombination (CSR), a region specific deletion recombination process, generates different immunoglobulin (Ig) isotypes by replacing one switch region with another. This process leads to enhanced functionality of immunoglobulins.[16][17]
- Class switch recombination (CSR), just like somatic hypermutation (SMH), requires the expression of activation-induced deaminase (AID) and both are dependent on creation of double-stranded DNA breaks (DSB) in the Ig loci.[18][19][20]
For more information on immunoglobulins, click here.
Pathogenesis
The pathogenesis of multiple myeloma is complex and probably is a result of multiple and multi-step oncogenic events such as hyperdiploidy, deregulation of cyclin D1 and interaction of myeloma cells with marrow environment. A brief description of events thought to play a role in pathogenesis of multiple myeloma is given here.
Environmental and hereditary factors
- The Key environmental and hereditary factors thought to confer a greater risk of developing multiple myeloma or play a part in pathogenesis are summarized in the table below.[8][21][22][23][24][25][26][27][28][29][30]
| Environmental and hereditary risk factors |
|---|
|
| * Likely influenced by environmental and behavioral confounding factors. |
Chromosomal aberrations
- Two major sets of chromosomal abnormalities seen in multiple myeloma are translocations with extensive IgH rearrangements and numerical aberrations, either trisomy or monosomy.[8][5]
Translocations
- Majority of translocations in multiple myeloma take place through class switch recombination (CSR). But few may occur through DH–JH recombination, possibly in early stages of B-cell development such as pre-B cell stage.[8][31]
- Majority of these translocations put oncogenes such as cyclin D1 (CCND1), CCND3, fibroblast growth factor receptor 3 (FGFR3), multiple myeloma SET domain (MMSET; also known as WHSC1), MAF and MAFB under the influence of enhancers present at Ig loci. .[5][8][32][33]
- These translocations cause over-expression of these oncogenes that in turn leads to dysregulation of cell-cycle such as increased cell survival, growth, progression and DNA repair. One of the key abnormality being the increased G1/S transition during the cell-cycle.[8][34]
- Many other translocations may occur in later phases of multiple myeloma. One important example is translocation of MYC, an oncogene that encodes transcription factors.[8][35][36]
Hyperdiploidy
- Gain of the odd numbered chromosomes including 3, 5, 7, 9, 11, 15, 19 and 21 is the other major abnormality observed in multiple myeloma.[5] [8]
- The mechanism of this gain phenomena is not well understood, one hypothesis being the gain of chromosome during single mitosis.[8]
| Chromosomal aberrations in multiple myeloma (MM) | ||
|---|---|---|
| Chromosomal Abnormality | Chromosome(s)/Protein(s) affected | Consequence |
| Trisomies | Odd-numbered chromosomes with the
exception of chromosomes 1, 13, and 21 |
|
| t(11;14)(q13;q32)
t(6;14q)(p21;32) t(12;14)(p13;q32) |
Cyclin D1
Cyclin D3 Cyclin D2 |
Over-expression; cell cycle dysregulation |
| t(4;14)(p16;q32) | FGFR3 or MMSET | Over-expression and activation; multiple myeloma cell proliferation/apoptosis prevention MMSET
probably linked to crucial transforming event |
| t(14;16)(q32;q23)
t(14;20)(q32;q11) t(8;14)(q24;q32) |
c-MAF | Over-expression; involvement in IL-4 regulation |
| del 17p13 | p53 | Cell-cycle dysregulation/apoptosis |
| Monosomy 14 | Chromosome 14 | |
| Chromosome 13 deletion and monosomy | Chromosome 13 | |
| Gain(1q21) | Chromosome 1 | |
| Abbreviations used: FGFR3:fibroblast growth factor receptor 3; MMSET:multiple myeloma SET domain; MAF:musculoaponeurotic fibrosarcoma oncogene homolog. | ||
Mutations in myeloma
- Studies have demonstrated the presence of approximately 35 mutations per sample in multiple myeloma. These mutations cause loss of tumor suppressors and NFKB alterations.[8]
Tumor suppressors
- These mutations result in cell-cycle dysregulation with an increase in G1/S transition. Some of these mutations are mentioned in the table below.[8][37][38][39]
- The loss of tumor suppressors allows the cells to survive and grow without check points.
| Tumor suppressor genes commonly affected in myeloma |
|---|
| FAM46C (family with sequence similarity 46, member C) |
| DIS3 (Exosome complex exonuclease RRP44) |
| CYLD (Cylindromatosis) |
| Baculoviral IAP repeat containing protein 2 (BIRC2; also known as cIAP1) |
| BIRC3 (Baculoviral IAP repeat containing protein 3) |
| tumor necrosis factor receptor associated factor 3 (TRAF3) |
| CDKN2C |
| CDKN2A |
| TP53 |
NFKB alterations
- NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex which regulates DNA transcription, production of cytokine and cell survival. NF-κB plays a key role in generating cellular responses to stimuli such as stress, free radicals, heavy metals, ultraviolet radiations, and foreign antigens. NF-κB is also crucial in response of the immune system towards infections.[40][41][42]
Pathophysiology of renal involvement
Abnormal antibody fragments are produced in multiple myeloma and are deposited in various organs, such as the kidneys. There are three major forms of renal damage in patients with multiple myeloma.
- Cast nephropathy: End-organ damage to the kidneys is typically due to light chain cast nephropathy. The pathophysiology of this type of renal involvement is based on light chain deposition in the renal tubules, which results in obstruction. Free light chains are readily filtered at the glomerulus and are reabsorbed in the proximal tubule of the nephron. This reabsorption occurs via the megalin-cubulin transport system.[43] In patients with multiple myeloma, there is excess production of free light chains, and the ability of the nephron to resorb light chains in the proximal tubule cannot meet the demands of the freely filtered light chains. This results in excess secretion of free light chains in the urine (known as Bence-Jones protein). Eosinophilic proteinaceous casts and crystalline structures can be seen. Cast formation occurs in the tubules due to excess abundance of free light chains that interact with Tamm-Horsfall proteins in the thick ascending loop of Henle.[43] Tubular obstruction ensues, triggering local inflammation which results in interstitial nephritis and fibrosis.[43] The onset of cast nephropathy can be very quick, requiring prompt treatment. Risk factors for development of cast nephropathy include monoclonal immunoglobulin secretion of >10 g/day, sepsis, and volume depletion.[44] Patients can also develop Fanconi syndrome, resulting in dysfunctional reabsorption ability by the proximal tubule, and type II renal tubular acidosis.
- Monoclonal immunoglobulin deposition disease (MIDD): In this subtype of renal involvement by multiple myeloma, the initial pathophysiological process is filtration of monoclonal immunoglobulins and subsequent deposition of immunoglobulins along the tubular or glomerular basement membrane.[44] Deposits of immunoglobulin can have a similar appearance as Kimmelstein-Wilson lesions (seen in diabetes). The immunoglobulins can appear fibroblast-like.
- Light chain amyloidosis: The pathophysiology of renal involvement by light chain amyloidosis begins with beta-pleated sheet formation in the tubules or glomeruli. Beta-pleated sheets form as a result of electrostatic interactions between heparan sulfate proteoglycan and amyloid proteins. Amyloid fibrils usually consist of immunoglobulin light chains (usually lambda light chain) and deposit in the basement membrane. The size of the fibrils vary from 7 to 10 nanometers. A diagnosis of this type of renal involvement is made by the visualization of apple green birefringence upon Congo red staining of the renal specimen.[44] It is frequently associated with nephrotic range proteinuria, in which greater than 3 grams of protein is excreted daily.
Pathophysiology of osseous involvement
The pathophysiology of bony involvement of multiple myeloma involves cytokines and cellular interactions.
- Cytokines: Multiple myeloma is one of the most common malignancies that creates lytic bony lesions. Other cancers that can create lytic bony lesions include renal cell carcinoma, lung cancer, breast cancer, thyroid cancer, and lymphoma. Lytic destruction has a distinct pathophysiology compared to the blastic destruction that is seen in prostate cancer. The pathophysiology of bony disease in multiple myeloma begins with stimulation of osteoclast production and suppression of osteoblast production. The steady state of bone metabolism is shifted in the direction of bone resorption. The molecular mechanism that governs osteoclast activation in multiple myeloma involves nuclear factor kappa B (NFkB), interleukin-3 (IL-3), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-a), and CXCL12, also known as stromal cell-derived factor 1 (SDF1).[45]
- Cellular interactions: At the cellular level, bone breakdown is governed by interactions between multiple myeloma cells, osteoclasts, osteoblasts, mesenchymal stem cells, T lymphocytes and dendritic cells. Multiple myeloma cells chemoattract hematopoietic cells such as dendritic cells, which produce osteoclastic factors that contribute to bone breakdown. Dendritic cells can also transdifferentiate into osteoclasts.[45] Multiple myeloma cells suppress osteoblast production by inhibiting expression of the transcription factor RUNX2, which is critical for osteoblast activity. The immune microenvironment thus plays a major role in the formation of lytic lesions in patients with multiple myeloma. Malignant plasma cells infiltrate hematopoietic sites such as the red bone marrow where they interfere with the production of normal blood cells.[1][2][3][46] The distribution of multiple myeloma mirrors that of red bone marrow in older individuals, and thus multiple myeloma is mostly encountered in the axial skeleton and proximal appendicular skeleton such as:[1]
- Vertebrae (most common)
- Ribs
- Skull
- Shoulder girdle
- Pelvis
- Long bones
- Extra skeletal structures (extraosseous myeloma) (rare)
Gross Pathology
-
Vertebrae in multiple myeloma
(Image courtesy of Melih Aktan M.D.) -
Calvarium in multiple myeloma.
(Image courtesy of Melih Aktan M.D.)
Microscopic Pathology
On microscopic histopathological analysis, multiple myeloma is characterized by the following:[4]
- Abundant eosinophilic cytoplasm
- Eccentrically placed nucleus
- Clock face morphology of the nucleus due to chromatin clumps around the edges
- Russell bodies which are eosinophilic, large (10-15 micrometres), homogenous immunoglobulin-containing inclusions
- Dutcher bodies which are PAS stain +ve intranuclear crystalline rods
- Shown below is a series of microscopic images seen in multiple myeloma:
-
![Multiple Myeloma slide showing plasma cells with large nucleus and scant cytoplasm [47]](/images/a/a5/Multiple_Myeloma.jpg)
Multiple Myeloma slide showing plasma cells with large nucleus and scant cytoplasm [47] -
Bone marrow aspiration in multiple myeloma.
(Image courtesy of Melih Aktan M.D.) -
Bone marrow biopsy in multiple myeloma.
(Image courtesy of Melih Aktan M.D.) -
Bone marrow in multiple myeloma.
(Image courtesy of Melih Aktan M.D.) -
Bone marrow in multiple myeloma.
(Image courtesy of Melih Aktan M.D.) -
![Multiple myeloma slide with intermediate magnification[4]](/images/4/40/Multiple_myeloma_intermed_mag.jpg)
Multiple myeloma slide with intermediate magnification[4] -
![Multiple myeloma slide with high magnification[4]](/images/d/d5/Multiple_myeloma.jpg)
Multiple myeloma slide with high magnification[4] -
![Multiple myeloma slide with russell bodies[4]](/images/a/ad/Russell_bodies.jpg)
Multiple myeloma slide with russell bodies[4]
![Multiple Myeloma slide showing plasma cells with large nucleus and scant cytoplasm [47]](/index.php/File:Multiple_Myeloma.jpg)
![Multiple myeloma slide with intermediate magnification[4]](/index.php/File:Multiple_myeloma_intermed_mag.jpg)
![Multiple myeloma slide with high magnification[4]](/index.php/File:Multiple_myeloma.jpg)
![Multiple myeloma slide with russell bodies[4]](/index.php/File:Russell_bodies.jpg)
References
- ↑ 1.0 1.1 1.2 Multiple myeloma. Radiopaedia (2015)http://radiopaedia.org/articles/multiple-myeloma-1 Accessed on September, 20th 2015
- ↑ 2.0 2.1 Multiple myeloma. Wikipedia (2015)https://en.wikipedia.org/wiki/Multiple_myeloma#Pathophysiology Accessed on September, 20th 2015
- ↑ 3.0 3.1 Multiple myeloma. Medlineplus (2015)https://www.nlm.nih.gov/medlineplus/multiplemyeloma.html Accessed on September, 20th 2015
- ↑ 4.0 4.1 4.2 4.3 4.4 Multiple myeloma. Librepathology (2015)http://www.wikidoc.org/index.php?title=Multiple_myeloma_pathophysiology&action=edit§ion=1 Accessed on September, 20th 2015
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Borrello I (November 2012). "Can we change the disease biology of multiple myeloma?". Leuk. Res. 36 Suppl 1: S3–12. doi:10.1016/S0145-2126(12)70003-6. PMC 3698609. PMID 23176722.
- ↑ 6.0 6.1 6.2 6.3 Chng WJ, Glebov O, Bergsagel PL, Kuehl WM (December 2007). "Genetic events in the pathogenesis of multiple myeloma". Best Pract Res Clin Haematol. 20 (4): 571–96. doi:10.1016/j.beha.2007.08.004. PMC 2198931. PMID 18070707.
- ↑ 7.0 7.1 7.2 7.3 Hengeveld PJ, Kersten MJ (February 2015). "B-cell activating factor in the pathophysiology of multiple myeloma: a target for therapy?". Blood Cancer J. 5: e282. doi:10.1038/bcj.2015.3. PMC 4349256. PMID 25723853.
- ↑ 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 Boyle EM, Davies FE, Leleu X, Morgan GJ (April 2014). "Understanding the multiple biological aspects leading to myeloma". Haematologica. 99 (4): 605–12. doi:10.3324/haematol.2013.097907. PMC 3971069. PMID 24688108.
- ↑ Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, Gravallese EM, Friend D, Grusby MJ, Alt F, Glimcher LH (July 2001). "Plasma cell differentiation requires the transcription factor XBP-1". Nature. 412 (6844): 300–7. doi:10.1038/35085509. PMID 11460154.
- ↑ Nutt SL, Taubenheim N, Hasbold J, Corcoran LM, Hodgkin PD (October 2011). "The genetic network controlling plasma cell differentiation". Semin. Immunol. 23 (5): 341–9. doi:10.1016/j.smim.2011.08.010. PMID 21924923.
- ↑ Boyle EM, Davies FE, Leleu X, Morgan GJ (April 2014). "Understanding the multiple biological aspects leading to myeloma". Haematologica. 99 (4): 605–12. doi:10.3324/haematol.2013.097907. PMC 3971069. PMID 24688108.
- ↑ Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, Gravallese EM, Friend D, Grusby MJ, Alt F, Glimcher LH (July 2001). "Plasma cell differentiation requires the transcription factor XBP-1". Nature. 412 (6844): 300–7. doi:10.1038/35085509. PMID 11460154.
- ↑ Nutt SL, Taubenheim N, Hasbold J, Corcoran LM, Hodgkin PD (October 2011). "The genetic network controlling plasma cell differentiation". Semin. Immunol. 23 (5): 341–9. doi:10.1016/j.smim.2011.08.010. PMID 21924923.
- ↑ 14.0 14.1 Eleonora Market, F. Nina Papavasiliou (2003) V(D)J Recombination and the Evolution of the Adaptive Immune System PLoS Biology1(1): e16.
- ↑ 15.0 15.1 Litman GW, Rast JP, Shamblott MJ; et al. (1993). "Phylogenetic diversification of immunoglobulin genes and the antibody repertoire". Mol. Biol. Evol. 10 (1): 60–72. PMID 8450761.
- ↑ Boyle EM, Davies FE, Leleu X, Morgan GJ (April 2014). "Understanding the multiple biological aspects leading to myeloma". Haematologica. 99 (4): 605–12. doi:10.3324/haematol.2013.097907. PMC 3971069. PMID 24688108.
- ↑ Nutt SL, Taubenheim N, Hasbold J, Corcoran LM, Hodgkin PD (October 2011). "The genetic network controlling plasma cell differentiation". Semin. Immunol. 23 (5): 341–9. doi:10.1016/j.smim.2011.08.010. PMID 21924923.
- ↑ Boyle EM, Davies FE, Leleu X, Morgan GJ (April 2014). "Understanding the multiple biological aspects leading to myeloma". Haematologica. 99 (4): 605–12. doi:10.3324/haematol.2013.097907. PMC 3971069. PMID 24688108.
- ↑ Keim C, Kazadi D, Rothschild G, Basu U (January 2013). "Regulation of AID, the B-cell genome mutator". Genes Dev. 27 (1): 1–17. doi:10.1101/gad.200014.112. PMC 3553278. PMID 23307864.
- ↑ González D, van der Burg M, García-Sanz R, Fenton JA, Langerak AW, González M, van Dongen JJ, San Miguel JF, Morgan GJ (November 2007). "Immunoglobulin gene rearrangements and the pathogenesis of multiple myeloma". Blood. 110 (9): 3112–21. doi:10.1182/blood-2007-02-069625. PMID 17634408.
- ↑ Morgan GJ, Davies FE, Linet M (July 2002). "Myeloma aetiology and epidemiology". Biomed. Pharmacother. 56 (5): 223–34. PMID 12199621.
- ↑ Wadhera RK, Rajkumar SV (October 2010). "Prevalence of monoclonal gammopathy of undetermined significance: a systematic review". Mayo Clin. Proc. 85 (10): 933–42. doi:10.4065/mcp.2010.0337. PMC 2947966. PMID 20713974.
- ↑ Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, Dispenzieri A, Kumar S, Clark RJ, Baris D, Hoover R, Rajkumar SV (May 2009). "Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study". Blood. 113 (22): 5412–7. doi:10.1182/blood-2008-12-194241. PMC 2689042. PMID 19179464.
- ↑ Wang SS, Voutsinas J, Chang ET, Clarke CA, Lu Y, Ma H, West D, Lacey JV, Bernstein L (July 2013). "Anthropometric, behavioral, and female reproductive factors and risk of multiple myeloma: a pooled analysis". Cancer Causes Control. 24 (7): 1279–89. doi:10.1007/s10552-013-0206-0. PMC 3684420. PMID 23568533.
- ↑ Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM (July 2007). "Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis". Lancet. 370 (9581): 59–67. doi:10.1016/S0140-6736(07)61050-2. PMID 17617273.
- ↑ Kachuri L, Demers PA, Blair A, Spinelli JJ, Pahwa M, McLaughlin JR, Pahwa P, Dosman JA, Harris SA (October 2013). "Multiple pesticide exposures and the risk of multiple myeloma in Canadian men". Int. J. Cancer. 133 (8): 1846–58. doi:10.1002/ijc.28191. PMID 23564249.
- ↑ Singh J, Dudley AW, Kulig KA (December 1990). "Increased incidence of monoclonal gammopathy of undetermined significance in blacks and its age-related differences with whites on the basis of a study of 397 men and one woman in a hospital setting". J. Lab. Clin. Med. 116 (6): 785–9. PMID 2246554.
- ↑ Kristinsson SY, Björkholm M, Goldin LR, Blimark C, Mellqvist UH, Wahlin A, Turesson I, Landgren O (November 2009). "Patterns of hematologic malignancies and solid tumors among 37,838 first-degree relatives of 13,896 patients with multiple myeloma in Sweden". Int. J. Cancer. 125 (9): 2147–50. doi:10.1002/ijc.24514. PMC 2737604. PMID 19582882.
- ↑ Broderick P, Chubb D, Johnson DC, Weinhold N, Försti A, Lloyd A, Olver B, Ma Y, Dobbins SE, Walker BA, Davies FE, Gregory WA, Childs JA, Ross FM, Jackson GH, Neben K, Jauch A, Hoffmann P, Mühleisen TW, Nöthen MM, Moebus S, Tomlinson IP, Goldschmidt H, Hemminki K, Morgan GJ, Houlston RS (November 2011). "Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk". Nat. Genet. 44 (1): 58–61. doi:10.1038/ng.993. PMC 5108406. PMID 22120009.
- ↑ Chubb D, Weinhold N, Broderick P, Chen B, Johnson DC, Försti A, Vijayakrishnan J, Migliorini G, Dobbins SE, Holroyd A, Hose D, Walker BA, Davies FE, Gregory WA, Jackson GH, Irving JA, Pratt G, Fegan C, Fenton JA, Neben K, Hoffmann P, Nöthen MM, Mühleisen TW, Eisele L, Ross FM, Straka C, Einsele H, Langer C, Dörner E, Allan JM, Jauch A, Morgan GJ, Hemminki K, Houlston RS, Goldschmidt H (October 2013). "Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk". Nat. Genet. 45 (10): 1221–1225. doi:10.1038/ng.2733. PMC 5053356. PMID 23955597.
- ↑ Walker BA, Wardell CP, Johnson DC, Kaiser MF, Begum DB, Dahir NB, Ross FM, Davies FE, Gonzalez D, Morgan GJ (April 2013). "Characterization of IGH locus breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pregerminal center B cells". Blood. 121 (17): 3413–9. doi:10.1182/blood-2012-12-471888. PMID 23435460.
- ↑ Chesi M, Nardini E, Brents LA, Schröck E, Ried T, Kuehl WM, Bergsagel PL (July 1997). "Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3". Nat. Genet. 16 (3): 260–4. doi:10.1038/ng0797-260. PMC 3901950. PMID 9207791.
- ↑ Fonseca R, Bergsagel PL, Drach J, Shaughnessy J, Gutierrez N, Stewart AK, Morgan G, Van Ness B, Chesi M, Minvielle S, Neri A, Barlogie B, Kuehl WM, Liebisch P, Davies F, Chen-Kiang S, Durie BG, Carrasco R, Sezer O, Reiman T, Pilarski L, Avet-Loiseau H (December 2009). "International Myeloma Working Group molecular classification of multiple myeloma: spotlight review". Leukemia. 23 (12): 2210–21. doi:10.1038/leu.2009.174. PMC 2964268. PMID 19798094.
- ↑ Brito JL, Walker B, Jenner M, Dickens NJ, Brown NJ, Ross FM, Avramidou A, Irving JA, Gonzalez D, Davies FE, Morgan GJ (January 2009). "MMSET deregulation affects cell cycle progression and adhesion regulons in t(4;14) myeloma plasma cells". Haematologica. 94 (1): 78–86. doi:10.3324/haematol.13426. PMC 2625417. PMID 19059936.
- ↑ Shou Y, Martelli ML, Gabrea A, Qi Y, Brents LA, Roschke A, Dewald G, Kirsch IR, Bergsagel PL, Kuehl WM (January 2000). "Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma". Proc. Natl. Acad. Sci. U.S.A. 97 (1): 228–33. PMC 26645. PMID 10618400.
- ↑ Nobuyoshi M, Kawano M, Tanaka H, Ishikawa H, Tanabe O, Iwato K, Asaoku H, Sakai A, Kuramoto A (April 1991). "Increased expression of the c-myc gene may be related to the aggressive transformation of human myeloma cells". Br. J. Haematol. 77 (4): 523–8. PMID 2025578.
- ↑ Walker BA, Leone PE, Chiecchio L, Dickens NJ, Jenner MW, Boyd KD, Johnson DC, Gonzalez D, Dagrada GP, Protheroe RK, Konn ZJ, Stockley DM, Gregory WM, Davies FE, Ross FM, Morgan GJ (October 2010). "A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value". Blood. 116 (15): e56–65. doi:10.1182/blood-2010-04-279596. PMID 20616218.
- ↑ Gonzalez-Paz N, Chng WJ, McClure RF, Blood E, Oken MM, Van Ness B, James CD, Kurtin PJ, Henderson K, Ahmann GJ, Gertz M, Lacy M, Dispenzieri A, Greipp PR, Fonseca R (February 2007). "Tumor suppressor p16 methylation in multiple myeloma: biological and clinical implications". Blood. 109 (3): 1228–32. doi:10.1182/blood-2006-05-024661. PMID 16840723.
- ↑ Seemann S, Maurici D, Olivier M, Caron de Fromentel C, Hainaut P (2004). "The tumor suppressor gene TP53: implications for cancer management and therapy". Crit Rev Clin Lab Sci. 41 (5–6): 551–83. doi:10.1080/10408360490504952. PMID 15603511.
- ↑ Gilmore TD (October 2006). "Introduction to NF-kappaB: players, pathways, perspectives". Oncogene. 25 (51): 6680–4. doi:10.1038/sj.onc.1209954. PMID 17072321.
- ↑ Perkins ND (January 2007). "Integrating cell-signalling pathways with NF-kappaB and IKK function". Nat. Rev. Mol. Cell Biol. 8 (1): 49–62. doi:10.1038/nrm2083. PMID 17183360.
- ↑ Tian B, Brasier AR (2003). "Identification of a nuclear factor kappa B-dependent gene network". Recent Prog. Horm. Res. 58: 95–130. PMID 12795416.
- ↑ 43.0 43.1 43.2 Finkel KW, Cohen EP, Shirali A, Abudayyeh A, American Society of Nephrology Onco-Nephrology Forum (2016). "Paraprotein-Related Kidney Disease: Evaluation and Treatment of Myeloma Cast Nephropathy". Clin J Am Soc Nephrol. 11 (12): 2273–2279. doi:10.2215/CJN.01640216. PMC 5142056. PMID 27526708.
- ↑ 44.0 44.1 44.2 Heher EC, Rennke HG, Laubach JP, Richardson PG (2013). "Kidney disease and multiple myeloma". Clin J Am Soc Nephrol. 8 (11): 2007–17. doi:10.2215/CJN.12231212. PMC 3817918. PMID 23868898.
- ↑ 45.0 45.1 Yaccoby S (2010). "Advances in the understanding of myeloma bone disease and tumour growth". Br J Haematol. 149 (3): 311–21. doi:10.1111/j.1365-2141.2010.08141.x. PMC 2864366. PMID 20230410.
- ↑ What is multiple myeloma. Canadian Cancer Society (2015) http://www.cancer.ca/en/cancer-information/cancer-type/multiple-myeloma/multiple-myeloma/?region=mb Accessed on September, 20th 2015
- ↑ http://picasaweb.google.com/mcmumbi/USMLEIIImages