Waldenström's macroglobulinemia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mirdula Sharma, MBBS [2]
Overview
Waldenström macroglobulinemia is an uncontrolled clonal proliferation of terminally differentiated B lymphocytes, which are normally involved in humoral immunity. Genes involved in the pathogenesis of Waldenström macroglobulinemia include MYD88-L265P, and CXCR4. The progression to Waldenström macroglobulinemia usually involves the MYD88/IRAK, and PI3K/Akt/mTOR molecular pathways. [1]
Pathophysiology
Pathogenesis
- Waldenström macroglobulinemia arises from terminally differentiated B lymphocytes, which are normally involved in humoral immunity.
- The exact pathogenesis of Waldenström macroglobulinemia is not completely understood; however, its familial pattern of involvement supports the role played by genetic factors in the pathogenesis of this disease.[2][3]
- Somatic mutations as well as chromosomal abnrmalities play a part in the pathogenesis of Waldenström macroglobulinemia:
- A mutation of the MYD88 gene has been found in more than 90% of patients with Waldenström macroglobulinemia.[4]
- Many cytogenetic abnormalities were reported in Waldenström macroglobulinemia patients including a deletion of the long arm of chromosome 6 (most common) and chromosome 20, trisomy 4 and 5, and monosomy 8.[5]
Molecular pathway alteration
- MYD88/IRAK:
- MYD88/IRAK pathway has an important role in the pathogenesis of waldenström macroglobulinemia.[6]
- The toll-like receptor and interleukin-1 receptor signaling recruits Interleukin-1 receptor associated kinase 4 to the receptor causing activation of transcription factors of the NF-kB family.
- Bruton tyrosine kinase (BTK) phosphorylation in waldenström macroglobulinemia cells promotes B cell overgrowth and survival.
- PI3K/Akt/mTOR
- Normally, the PI3K/Akt/mTOR pathway signals to inhibit apoptosis.
- In waldenström macroglobulinemia, an activating mutation of the PI3K/Akt/mTOR pathway promotes growth and proliferation of tumor cells.
- In waldenström macroglobulinemia, following factors affect PI3K/Akt/mTOR pathway signaling:
- Activators:
- MYD88 L265P mutation
- Bone marrow microenvironment - through the cytokines such as insulin-like growth factor (IGF- 1) or stromal- derived factor (SDF-1)
- PTEN - a negative regulator of the PI3K/Akt/mTOR pathway is decreased which causes unopposed activation of the PI3K/Akt/mTOR pathway in waldenström macroglobulinemia.
- Inhibitor:
- Akt - inhibited by perifosine
- mTOR - inhibited by RAD001
Genetics
- Development of waldenström macroglobulinemia is the result of multiple gene mutations.[1]
- Genes involved in pathogenesis of waldenström macroglobulinemia are:
- MYD88-L265P in chromosome 3p22.2
- MYD88: The activating point mutation of MYD88 augments growth and survival of both normal and neoplastic B cells by preventing apoptosis. Point mutation of MYD88 leads to leucine (L) to proline (P) substitution in codon 265 (L265P) of MYD88 and produces constantly overactive protein causing proliferation of malignant cells that should normally undergo apoptosis.[1][7]
- Monoclonal gammopathy of undetermined significance patients found to have MYD88 L265P mutation have significantly higher risk of progression to waldenström macroglobulinemia or to other lymphoproliferative disorders.[6]
- CXCR4
- Patients with waldenström's macroglobulinemia with co-existing mutation of MYD88 & CXCR4 are more likely to have hyperviscosity syndrome and bone marrow involvement.[1]
Epigenetics
- Three most common epigenetic causes are DNA methylation, histone acetylation, and non-coding RNAs such as miRNAs.[6]
- Upregulation of miRNAs 155, 184, 206, 363, 494, and 542-3p occurs in waldenström macroglobulinemia; among which miRNA-155 has a crucial role in tumor cell growth and proliferation in waldenström macroglobulinemia.
- Gene transcription through histone acetylation occurs following increased expression of miRNA-206 and reduced expression of miRNA-9.
Associated Conditions
Several studies showed an increased incidence of following second cancers in patients with waldenström macroglobulinemia:[8]
- Diffuse large B-cell lymphoma
- Myelodysplastic syndrome/Acute myeloid leukemia
- Brain tumor
- Renal MALT lymphoma [9]
Microscopic Pathology
Following are the images of microscopic histology of waldenström's macroglobulinemia:
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Rouleaux formation, plasmacytoid cells, and lymphoid cells in the PBF
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Uni-binucleated plasmacytoid cells in the PBF
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Plasmacytoid cells in the bone marrow aspirates
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Tetranucleated plasmacytoid/plasma cell and lymphoid cell in the bone marrow aspirates
Immunohistochemistry
Malignant cells in waldenström macroglobulinemia:[1]
- Express pan B-cell antigens (CD19, CD20, CD22, CD79A), and CD5
- Variable expression of CD11c, CD43, CD25
- Most express IgM surface immunoglobulin, while fewer express IgG or IgA and lack IgD
References
- ↑ 1.0 1.1 1.2 1.3 1.4 Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH, Kohlhammer H, Xu W, Yang Y, Zhao H, Shaffer AL, Romesser P, Wright G, Powell J, Rosenwald A, Muller-Hermelink HK, Ott G, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Staudt LM (2011). "Oncogenically active MYD88 mutations in human lymphoma". Nature. 470 (7332): 115–9. doi:10.1038/nature09671. PMID 21179087.
- ↑ Royer RH, Koshiol J, Giambarresi TR, Vasquez LG, Pfeiffer RM, McMaster ML (2010). "Differential characteristics of Waldenström macroglobulinemia according to patterns of familial aggregation". Blood. 115 (22): 4464–71. doi:10.1182/blood-2009-10-247973. PMC 2881498. PMID 20308603.
- ↑ Treon SP, Hunter ZR, Aggarwal A, Ewen EP, Masota S, Lee C; et al. (2006). "Characterization of familial Waldenstrom's macroglobulinemia". Ann Oncol. 17 (3): 488–94. doi:10.1093/annonc/mdj111. PMID 16357024.
- ↑ Steven P. Treon, Lian Xu, Guang Yang, Yangsheng Zhou, Xia Liu, Yang Cao, Patricia Sheehy, Robert J. Manning, Christopher J. Patterson, Christina Tripsas, Luca Arcaini, Geraldine S. Pinkus, Scott J. Rodig, Aliyah R. Sohani, Nancy Lee Harris, Jason M. Laramie, Donald A. Skifter, Stephen E. Lincoln & Zachary R. Hunter (2012). "MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia". The New England journal of medicine. 367 (9): 826–833. doi:10.1056/NEJMoa1200710. PMID 22931316. Unknown parameter
|month=ignored (help) - ↑ Roelandt F. J. Schop, W. Michael Kuehl, Scott A. Van Wier, Gregory J. Ahmann, Tammy Price-Troska, Richard J. Bailey, Syed M. Jalal, Ying Qi, Robert A. Kyle, Philip R. Greipp & Rafael Fonseca (2002). "Waldenstrom macroglobulinemia neoplastic cells lack immunoglobulin heavy chain locus translocations but have frequent 6q deletions". Blood. 100 (8): 2996–3001. doi:10.1182/blood.V100.8.2996. PMID 12351413. Unknown parameter
|month=ignored (help) - ↑ 6.0 6.1 6.2 Waldenström macroglobulinemia. International Waldenström Macroglobulinemia foundation (2015)http://www.iwmf.com/sites/default/files/docs/WM_Review_Ghobrial_Jan2014.pdf Accessed on November 12, 2015
- ↑ Waldenström macroglobulinemia. Genetics Home Reference (2015)http://ghr.nlm.nih.gov/condition/waldenstrom-macroglobulinemia Accessed on November 9, 2015
- ↑ Morra E, Varettoni M, Tedeschi A, Arcaini L, Ricci F, Pascutto C, Rattotti S, Vismara E, Paris L, Cazzola M (2013). "Associated cancers in Waldenström macroglobulinemia: clues for common genetic predisposition". Clin Lymphoma Myeloma Leuk. 13 (6): 700–3. doi:10.1016/j.clml.2013.05.008. PMID 24070824.
- ↑ Chi PJ, Pei SN, Huang TL, Huang SC, Ng HY, Lee CT (2014). "Renal MALT lymphoma associated with Waldenström macroglobulinemia". J. Formos. Med. Assoc. 113 (4): 255–7. doi:10.1016/j.jfma.2011.02.007. PMID 24685302.