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
Pathogenesis
Waldenström's macroglobulinemia arises from B lymphocyte, a type of white blood cell which is involved in humoral immunity.
Genetics
Although believed to be a sporadic disease, studies have shown increased susceptibility within families, indicating a genetic component.[1][2] A mutation in gene MYD88 has been found to occur frequently in patients.[3] WM cells show only minimal changes in cytogenetic and gene expression profiling|gene expression studies. Their miRNA signature however differs from their normal counterpart. It is therefore believed that epigenetic modifications play a crucial role in the disease.[4]
Comparative genomic hybridization identified the following chromosomal abnormalities: deletions of 6q23 and 13q14, and gains of 3q13-q28, 6p and 18q.[5] FGFR3 is overexpressed.[6] The following signalling pathways have been implicated:
- CD154/CD40[7]
- Akt[8]
- ubiquitination, p53 activation, cytochrome c release[9]
- NF-κB[10][11]
- WNT/beta-catenin[12]
- mTOR[13]
- ERK[10]
- MAPK[14]
- Bcl-2[15]
The protein Src tyrosine kinase is overexpressed in Waldenström macroglobulinemia cells compared with control B cells.[16] Inhibition of Src arrests the cell cycle at phase G1 and has little effect on the survival of WM or normal cells.
MicroRNAs involved in Waldenström's:[17][18]
- increased expression of miRNAs-363*,[19] -206,[20] -494,[21] -155,[22] -184,[23] -542–3p.[24]
- decreased expression of miRNA-9*.[25]
MicroRNA-155 regulates the proliferation and growth of WM cells in vitro and in vivo, by inhibiting MAPK/ERK, PI3/AKT, and NF-κB pathways.
In WM-cells, histone deacetylases and histone-modifying genes are de-regulated.[26]
Bone marrow tumour cells express the following antigen targets CD20 (98.3%), CD22 (88.3%), CD40 (83.3%), CD52 (77.4%), IgM (83.3%), MUC1 core protein (57.8%), and 1D10 (50%).[27]
Associated Conditions
Gross Pathology
Micropathology
References
- ↑ McMaster, M. (2003). "Familial Waldenstrom's macroglobulinemia". Seminars in oncology. 30 (2): 146–152. doi:10.1053/sonc.2003.50063. PMID 12720125.
- ↑ McMaster, M.; Goldin, L.; Bai, Y.; Ter-Minassian, M.; Boehringer, S.; Giambarresi, T.; Vasquez, L.; Tucker, M. (2006). "Genomewide linkage screen for Waldenstrom macroglobulinemia susceptibility loci in high-risk families". American Journal of Human Genetics. 79 (4): 695–701. doi:10.1086/507687. PMC 1592553. PMID 16960805.
- ↑ Treon, S. P.; Xu, L.; Yang, G.; Zhou, Y.; Liu, X.; Cao, Y.; Sheehy, P.; Manning, R. J.; Patterson, C. J.; Tripsas, C.; Arcaini, L.; Pinkus, G. S.; Rodig, S. J.; Sohani, A. R.; Harris, N. L.; Laramie, J. M.; Skifter, D. A.; Lincoln, S. E.; Hunter, Z. R. (2012). "MYD88 L265P Somatic Mutation in Waldenström's Macroglobulinemia". New England Journal of Medicine. 367 (9): 826–833. doi:10.1056/NEJMoa1200710. PMID 22931316.
- ↑ Sacco, A.; Issa, G. C.; Zhang, Y.; Liu, Y.; Maiso, P.; Ghobrial, I. M.; Roccaro, A. M. (2010). "Epigenetic modifications as key regulators of Waldenstrom's Macroglobulinemia biology". Journal of Hematology & Oncology. 3: 38. doi:10.1186/1756-8722-3-38. PMC 2964547. PMID 20929526.
- ↑ Braggio, E.; Keats, J. J.; Leleu, X.; Van Wier, S. V.; Jimenez-Zepeda, V. H.; Schop, R. F. J.; Chesi, M.; Barrett, M.; Stewart, A. K.; Dogan, A.; Bergsagel, P. L.; Ghobrial, I. M.; Fonseca, R. (2009). "High-Resolution Genomic Analysis in Waldenström's Macroglobulinemia Identifies Disease-Specific and Common Abnormalities with Marginal Zone Lymphomas". Clinical Lymphoma, Myeloma & Leukemia. 9 (1): 39–42. doi:10.3816/CLM.2009.n.009. PMC 3646570. PMID 19362969.
- ↑ Azab, A. K.; Azab, F.; Quang, P.; Maiso, P.; Sacco, B.; Ngo, A.; Liu, H. T.; Zhang, Y.; Morgan, Y.; Roccaro, A. M.; Ghobrial, I. M. (2011). "FGFR3 is overexpressed Waldenstrom macroglobulinemia and its inhibition by Dovitinib induces apoptosis, and overcomes stroma-induced proliferation". Clinical Cancer Research. 17 (13): 4389–4399. doi:10.1158/1078-0432.CCR-10-2772. PMID 21521775.
- ↑ http://www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=26&abstractID=4297
- ↑ Leleu, X.; Jia, X.; Runnels, J.; Ngo, H.; Moreau, A.; Farag, M.; Spencer, J.; Pitsillides, C.; Hatjiharissi, E.; Roccaro, A.; O'Sullivan, G.; McMillin, D. W.; Moreno, D.; Kiziltepe, T.; Carrasco, R.; Treon, S. P.; Hideshima, T.; Anderson, K. C.; Lin, C. P.; Ghobrial, I. M. (2007). "The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia". Blood. 110 (13): 4417–4426. doi:10.1182/blood-2007-05-092098. PMC 2234792. PMID 17761832.
- ↑ Mensah-Osman, E.; Al-Katib, A.; Dandashi, M.; Mohammad, R. (2003). "XK469, a topo IIbeta inhibitor, induces apoptosis in Waldenstrom's macroglobulinemia through multiple pathways". International journal of oncology. 23 (6): 1637–1644. doi:10.3892/ijo.23.6.1637. PMID 14612935.
- ↑ 10.0 10.1 Leleu, X.; Eeckhoute, J.; Jia, X.; Roccaro, A.; Moreau, A.; Farag, M.; Sacco, A.; Ngo, H.; Runnels, J.; Melhem, M. R.; Burwick, N.; Azab, A.; Azab, F.; Hunter, Z.; Hatjiharissi, E.; Carrasco, D. R.; Treon, S. P.; Witzig, T. E.; Hideshima, T.; Brown, M.; Anderson, K. C.; Ghobrial, I. M. (2008). "Targeting NF-kappaB in Waldenstrom macroglobulinemia". Blood. 111 (10): 5068–5077. doi:10.1182/blood-2007-09-115170. PMC 2384134. PMID 18334673.
- ↑ Braggio, E.; Keats, J.; Leleu, X.; Van Wier, S.; Jimenez-Zepeda, V.; Valdez, R.; Schop, R.; Price-Troska, T.; Henderson, K.; Sacco, A.; Azab, F.; Greipp, P.; Gertz, M.; Hayman, S.; Rajkumar, S. V.; Carpten, J.; Chesi, M.; Barrett, M.; Stewart, A. K.; Dogan, A.; Bergsagel, P. L.; Ghobrial, I. M.; Fonseca, R. (2009). "Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Waldenstrom's macroglobulinemia". Cancer Research. 69 (8): 3579–3588. doi:10.1158/0008-5472.CAN-08-3701. PMC 2782932. PMID 19351844.
- ↑ Gutiérrez, N.; Ocio, E.; De Las Rivas, J.; Maiso, P.; Delgado, M.; Fermiñán, E.; Arcos, M.; Sánchez, M.; Hernández, J.; San Miguel, J. F. (2007). "Gene expression profiling of B lymphocytes and plasma cells from Waldenström's macroglobulinemia: comparison with expression patterns of the same cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals". Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 21 (3): 541–549. doi:10.1038/sj.leu.2404520. PMID 17252022.
- ↑ Burwick, N.; Roccaro, A.; Leleu, X.; Ghobrial, I. (2008). "Targeted therapies in Waldenström macroglobulinemia". Current opinion in investigational drugs (London, England : 2000). 9 (6): 631–637. PMID 18516762.
- ↑ Chng, W.; Schop, R.; Price-Troska, T.; Ghobrial, I.; Kay, N.; Jelinek, D.; Gertz, M.; Dispenzieri, A.; Lacy, M.; Kyle, R. A.; Greipp, P. R.; Tschumper, R. C.; Fonseca, R.; Bergsagel, P. L. (2006). "Gene-expression profiling of Waldenstrom macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma". Blood. 108 (8): 2755–2763. doi:10.1182/blood-2006-02-005488. PMC 1895596. PMID 16804116.
- ↑ Nichols, G.; Stein, C. (2003). "Modulation of the activity of Bcl-2 in Waldenstrom's macroglobulinemia using antisense oligonucleotides". Seminars in oncology. 30 (2): 297–299. doi:10.1053/sonc.2003.50045. PMID 12720156.
- ↑ Ngo, H.; Azab, A.; Farag, M.; Jia, X.; Melhem, M.; Runnels, J.; Roccaro, A.; Azab, F.; Sacco, A.; Leleu, X.; Anderson, K. C.; Ghobrial, I. M. (2009). "Src tyrosine kinase regulates adhesion and chemotaxis in Waldenstrom macroglobulinemia". Clinical cancer research : an official journal of the American Association for Cancer Research. 15 (19): 6035–6041. doi:10.1158/1078-0432.CCR-09-0718. PMC 2990685. PMID 19755386.
- ↑ Vacca, A.; Dammacco, F. (2009). "MicroRNAs to know in Waldenstrom macroglobulinemia". Blood. 113 (18): 4133–4134. doi:10.1182/blood-2009-01-199828. PMID 19406998.
- ↑ Roccaro, A.; Sacco, A.; Chen, C.; Runnels, J.; Leleu, X.; Azab, F.; Azab, A.; Jia, X.; Ngo, H.; Melhem, M. R.; Burwick, N.; Varticovski, L.; Novina, C. D.; Rollins, B. J.; Anderson, K. C.; Ghobrial, I. M. (2009). "MicroRNA expression in the biology, prognosis, and therapy of Waldenström macroglobulinemia". Blood. 113 (18): 4391–4402. doi:10.1182/blood-2008-09-178228. PMC 2943754. PMID 19074725.
- ↑ http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000764
- ↑ http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000490
- ↑ http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0003134
- ↑ http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000681
- ↑ http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000481
- ↑ http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0003686
- ↑ http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000466
- ↑ Roccaro, A.; Sacco, A.; Jia, X.; Azab, A.; Maiso, P.; Ngo, H.; Azab, F.; Runnels, J.; Quang, P.; Ghobrial, I. M. (2010). "microRNA-dependent modulation of histone acetylation in Waldenström macroglobulinemia". Blood. 116 (9): 1506–1514. doi:10.1182/blood-2010-01-265686. PMC 2938840. PMID 20519629.
- ↑ Treon, S.; Kelliher, A.; Keele, B.; Frankel, S.; Emmanouilides, C.; Kimby, E.; Schlossman, R.; Mitsiades, N.; Mitsiades, C.; Preffer, F.; Anderson, K. C. (2003). "Expression of serotherapy target antigens in Waldenstrom's macroglobulinemia: therapeutic applications and considerations". Seminars in oncology. 30 (2): 248–252. doi:10.1053/sonc.2003.50047. PMID 12720146.