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| __NOTOC__
| | The clinical manifestations of Waldenström Macroglobulinemia depend on two different factors. |
| {{Waldenström's macroglobulinemia}}
| | *Hyperviscosity syndrome & vascular complications due to secretion of Monoclonal igM. |
| {{CMG}} {{AE}}{{MGS}}
| | :*IgM paraprotein occasionally has: |
| ==Overview==
| | :*Rheumatoid factor activity, |
| == Pathogenesis ==
| | :*antimyelin activity that can contribute to peripheral neuropathy, and |
| Waldenström's macroglobulinemia arises from B lymphocyte, a type of white blood cell which is involved in humoral immunity.
| | :*Immunologically related lupus anticoagulant activity. |
| ==Genetics==
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| Although believed to be a sporadic disease, studies have shown increased susceptibility within families, indicating a genetic component.<ref>{{Cite journal| last1 = McMaster | first1 = M.| title = Familial Waldenstrom's macroglobulinemia| journal = Seminars in oncology| volume = 30| issue = 2| pages = 146–152| year = 2003| pmid = 12720125| doi = 10.1053/sonc.2003.50063}}</ref><ref>{{Cite journal| last1 = McMaster | first1 = M.| last2 = Goldin | first2 = L.| last3 = Bai | first3 = Y.| last4 = Ter-Minassian | first4 = M.| last5 = Boehringer | first5 = S.| last6 = Giambarresi | first6 = T.| last7 = Vasquez | first7 = L.| last8 = Tucker | first8 = M.| title = Genomewide linkage screen for Waldenstrom macroglobulinemia susceptibility loci in high-risk families| journal = American Journal of Human Genetics| volume = 79| issue = 4| pages = 695–701| year = 2006| pmid = 16960805| pmc = 1592553| doi = 10.1086/507687}}</ref> A mutation in gene MYD88 has been found to occur frequently in patients.<ref>{{Cite journal | last1 = Treon | first1 = S. P. | last2 = Xu | first2 = L. | last3 = Yang | first3 = G. | last4 = Zhou | first4 = Y. | last5 = Liu | first5 = X. | last6 = Cao | first6 = Y. | last7 = Sheehy | first7 = P. | last8 = Manning | first8 = R. J. | last9 = Patterson | first9 = C. J. | last10 = Tripsas | doi = 10.1056/NEJMoa1200710 | first10 = C. | last11 = Arcaini | first11 = L. | last12 = Pinkus | first12 = G. S. | last13 = Rodig | first13 = S. J. | last14 = Sohani | first14 = A. R. | last15 = Harris | first15 = N. L. | last16 = Laramie | first16 = J. M. | last17 = Skifter | first17 = D. A. | last18 = Lincoln | first18 = S. E. | last19 = Hunter | first19 = Z. R. | title = MYD88 L265P Somatic Mutation in Waldenström's Macroglobulinemia | journal = New England Journal of Medicine | volume = 367 | issue = 9 | pages = 826–833 | year = 2012 | pmid = 22931316 | pmc = }}</ref> 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 [[Epigenetics|epigenetic]] modifications play a crucial role in the disease.<ref>{{Cite journal | doi = 10.1186/1756-8722-3-38 | last1 = Sacco | first1 = A. | last2 = Issa | first2 = G. C. | last3 = Zhang | first3 = Y. | last4 = Liu | first4 = Y. | last5 = Maiso | first5 = P. | last6 = Ghobrial | first6 = I. M. | last7 = Roccaro | first7 = A. M. | title = Epigenetic modifications as key regulators of Waldenstrom's Macroglobulinemia biology | journal = Journal of Hematology & Oncology | volume = 3 | pages = 38 | year = 2010 | pmid = 20929526 | pmc = 2964547}}</ref>
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| [[Comparative genomic hybridization]] identified the following [[chromosomal abnormalities]]: deletions of 6q23 and 13q14, and gains of 3q13-q28, 6p and 18q.<ref>{{Cite journal| last1 = Braggio | first1 = E.| last2 = Keats | first2 = J. J.| last3 = Leleu | first3 = X.| last4 = Van Wier | first4 = S. V.| last5 = Jimenez-Zepeda | first5 = V. H.| last6 = Schop | first6 = R. F. J.| last7 = Chesi | first7 = M.| last8 = Barrett | first8 = M.| last9 = Stewart | first9 = A. K.| last10 = Dogan | first10 = A.| last11 = Bergsagel | first11 = P. L.| last12 = Ghobrial | first12 = I. M.| last13 = Fonseca | first13 = R.| title = High-Resolution Genomic Analysis in Waldenström's Macroglobulinemia Identifies Disease-Specific and Common Abnormalities with Marginal Zone Lymphomas| journal = Clinical Lymphoma, Myeloma & Leukemia| volume = 9| issue = 1| pages = 39–42| year = 2009| pmid = 19362969| pmc = 3646570| doi = 10.3816/CLM.2009.n.009}}</ref> [[FGFR3]] is overexpressed.<ref>{{Cite journal | last1 = Azab | first1 = A. K. | last2 = Azab | first2 = F. | last3 = Quang | first3 = P. | last4 = Maiso | first4 = P. | last5 = Sacco | first5 = B. | last6 = Ngo | first6 = A. | last7 = Liu | first7 = H. T. | last8 = Zhang | first8 = Y. | last9 = Morgan | first9 = Y. | last10 = Roccaro | first10 = A. M. | last11 = Ghobrial | first11 = I. M. | title = FGFR3 is overexpressed Waldenstrom macroglobulinemia and its inhibition by Dovitinib induces apoptosis, and overcomes stroma-induced proliferation | doi = 10.1158/1078-0432.CCR-10-2772 | journal = Clinical Cancer Research | year = 2011 | pmid = 21521775 | volume=17 | issue=13 | pages=4389–4399}}</ref>
| | *Infiltration of bone marrow, spleen and lymph nodes by neoplastic lymphoplasmacytic cells. |
| The following signalling pathways have been implicated:
| | :*Less commonly, infiltration of liver, lungs, GI tract, kidneys, skin, eyes, and central nervous system (CNS) can also occur. |
| *[[CD154]]/[[CD40]]<ref>http://www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=26&abstractID=4297</ref>
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| *[[Akt]]<ref>{{Cite journal| last1 = Leleu | first1 = X.| last2 = Jia | first2 = X.| last3 = Runnels | first3 = J.| last4 = Ngo | first4 = H.| last5 = Moreau | first5 = A.| last6 = Farag | first6 = M.| last7 = Spencer | first7 = J.| last8 = Pitsillides | first8 = C.| last9 = Hatjiharissi | first9 = E.| last10 = Roccaro | first10 = A.| last11 = O'Sullivan | first11 = G.| last12 = McMillin | first12 = D. W.| last13 = Moreno | first13 = D.| last14 = Kiziltepe | first14 = T.| last15 = Carrasco | first15 = R.| last16 = Treon | first16 = S. P.| last17 = Hideshima | first17 = T.| last18 = Anderson | first18 = K. C.| last19 = Lin | first19 = C. P.| last20 = Ghobrial | first20 = I. M.| title = The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia| journal = Blood| volume = 110| issue = 13| pages = 4417–4426| year = 2007| pmid = 17761832| pmc = 2234792| doi = 10.1182/blood-2007-05-092098}}</ref>
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| *[[ubiquitination]], [[p53]] activation, [[cytochrome c]] release<ref>{{Cite journal| last1 = Mensah-Osman | first1 = E.| last2 = Al-Katib | first2 = A.| last3 = Dandashi | first3 = M.| last4 = Mohammad | first4 = R.| title = XK469, a topo IIbeta inhibitor, induces apoptosis in Waldenstrom's macroglobulinemia through multiple pathways| journal = International journal of oncology| volume = 23| issue = 6| pages = 1637–1644| year = 2003| pmid = 14612935 | doi=10.3892/ijo.23.6.1637}}</ref>
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| *[[NF-κB]]<ref name="PMID 18334673">{{Cite journal| last1 = Leleu | first1 = X.| last2 = Eeckhoute | first2 = J.| last3 = Jia | first3 = X.| last4 = Roccaro | first4 = A.| last5 = Moreau | first5 = A.| last6 = Farag | first6 = M.| last7 = Sacco | first7 = A.| last8 = Ngo | first8 = H.| last9 = Runnels | first9 = J.| last10 = Melhem | first10 = M. R.| last11 = Burwick | first11 = N.| last12 = Azab | first12 = A.| last13 = Azab | first13 = F.| last14 = Hunter | first14 = Z.| last15 = Hatjiharissi | first15 = E.| last16 = Carrasco | first16 = D. R.| last17 = Treon | first17 = S. P.| last18 = Witzig | first18 = T. E.| last19 = Hideshima | first19 = T.| last20 = Brown | first20 = M.| last21 = Anderson | first21 = K. C.| last22 = Ghobrial | first22 = I. M.| title = Targeting NF-kappaB in Waldenstrom macroglobulinemia| journal = Blood| volume = 111| issue = 10| pages = 5068–5077| year = 2008| pmid = 18334673| pmc = 2384134| doi = 10.1182/blood-2007-09-115170}}</ref><ref>{{Cite journal| last1 = Braggio | first1 = E.| last2 = Keats | first2 = J.| last3 = Leleu | first3 = X.| last4 = Van Wier | first4 = S.| last5 = Jimenez-Zepeda | first5 = V.| last6 = Valdez | first6 = R.| last7 = Schop | first7 = R.| last8 = Price-Troska | first8 = T.| last9 = Henderson | first9 = K.| last10 = Sacco | first10 = A.| last11 = Azab | first11 = F.| last12 = Greipp | first12 = P.| last13 = Gertz | first13 = M.| last14 = Hayman | first14 = S.| last15 = Rajkumar | first15 = S. V.| last16 = Carpten | first16 = J.| last17 = Chesi | first17 = M.| last18 = Barrett | first18 = M.| last19 = Stewart | first19 = A. K.| last20 = Dogan | first20 = A.| last21 = Bergsagel | first21 = P. L.| last22 = Ghobrial | first22 = I. M.| last23 = Fonseca | first23 = R.| title = Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Waldenstrom's macroglobulinemia| journal = Cancer Research| volume = 69| issue = 8| pages = 3579–3588| year = 2009| pmid = 19351844| pmc = 2782932| doi = 10.1158/0008-5472.CAN-08-3701}}</ref>
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| *[[Wnt signaling pathway|WNT]]/[[beta-catenin]]<ref>{{Cite journal| last1 = Gutiérrez | first1 = N.| last2 = Ocio | first2 = E.| last3 = De Las Rivas | first3 = J.| last4 = Maiso | first4 = P.| last5 = Delgado | first5 = M.| last6 = Fermiñán | first6 = E.| last7 = Arcos | first7 = M.| last8 = Sánchez | first8 = M.| last9 = Hernández | first9 = J.| last10 = San Miguel | first10 = J. F.| title = 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| journal = Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K| volume = 21| issue = 3| pages = 541–549| year = 2007| pmid = 17252022| doi = 10.1038/sj.leu.2404520}}</ref>
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| *mTOR<ref>{{Cite journal| last1 = Burwick | first1 = N.| last2 = Roccaro | first2 = A.| last3 = Leleu | first3 = X.| last4 = Ghobrial | first4 = I.| title = Targeted therapies in Waldenström macroglobulinemia| journal = Current opinion in investigational drugs (London, England : 2000)| volume = 9| issue = 6| pages = 631–637| year = 2008| pmid = 18516762}}</ref>
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| *[[Extracellular signal-regulated kinases|ERK]]<ref name="PMID 18334673"/> | |
| *[[MAPK]]<ref>{{Cite journal| last1 = Chng | first1 = W.| last2 = Schop | first2 = R.| last3 = Price-Troska | first3 = T.| last4 = Ghobrial | first4 = I.| last5 = Kay | first5 = N.| last6 = Jelinek | first6 = D.| last7 = Gertz | first7 = M.| last8 = Dispenzieri | first8 = A.| last9 = Lacy | first9 = M.| last10 = Kyle | first10 = R. A.| last11 = Greipp | first11 = P. R.| last12 = Tschumper | first12 = R. C.| last13 = Fonseca | first13 = R.| last14 = Bergsagel | first14 = P. L.| title = Gene-expression profiling of Waldenstrom macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma| journal = Blood| volume = 108| issue = 8| pages = 2755–2763| year = 2006| pmid = 16804116| pmc = 1895596| doi = 10.1182/blood-2006-02-005488}}</ref>
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| *[[Bcl-2]]<ref>{{Cite journal| last1 = Nichols | first1 = G.| last2 = Stein | first2 = C.| title = Modulation of the activity of Bcl-2 in Waldenstrom's macroglobulinemia using antisense oligonucleotides| journal = Seminars in oncology| volume = 30| issue = 2| pages = 297–299| year = 2003| pmid = 12720156| doi = 10.1053/sonc.2003.50045}}</ref>
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| The protein [[Src (gene)|Src tyrosine kinase]] is overexpressed in Waldenström macroglobulinemia cells compared with control B cells.<ref>{{Cite journal| last1 = Ngo | first1 = H.| last2 = Azab | first2 = A.| last3 = Farag | first3 = M.| last4 = Jia | first4 = X.| last5 = Melhem | first5 = M.| last6 = Runnels | first6 = J.| last7 = Roccaro | first7 = A.| last8 = Azab | first8 = F.| last9 = Sacco | first9 = A.| last10 = Leleu | first10 = X.| last11 = Anderson | first11 = K. C.| last12 = Ghobrial | first12 = I. M.| title = Src tyrosine kinase regulates adhesion and chemotaxis in Waldenstrom macroglobulinemia| journal = Clinical cancer research : an official journal of the American Association for Cancer Research| volume = 15| issue = 19| pages = 6035–6041| year = 2009| pmid = 19755386| pmc = 2990685| doi = 10.1158/1078-0432.CCR-09-0718}}</ref> Inhibition of Src arrests the [[cell cycle]] at phase G<sub>1</sub> and has little effect on the survival of WM or normal cells.
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| [[MicroRNA]]s involved in Waldenström's:<ref>{{Cite journal| last1 = Vacca | first1 = A.| last2 = Dammacco | first2 = F.| title = MicroRNAs to know in Waldenstrom macroglobulinemia| journal = Blood| volume = 113| issue = 18| pages = 4133–4134| year = 2009| pmid = 19406998| doi = 10.1182/blood-2009-01-199828}}</ref><ref>{{Cite journal| last1 = Roccaro | first1 = A.| last2 = Sacco | first2 = A.| last3 = Chen | first3 = C.| last4 = Runnels | first4 = J.| last5 = Leleu | first5 = X.| last6 = Azab | first6 = F.| last7 = Azab | first7 = A.| last8 = Jia | first8 = X.| last9 = Ngo | first9 = H.| last10 = Melhem | first10 = M. R.| last11 = Burwick | first11 = N.| last12 = Varticovski | first12 = L.| last13 = Novina | first13 = C. D.| last14 = Rollins | first14 = B. J.| last15 = Anderson | first15 = K. C.| last16 = Ghobrial | first16 = I. M.| title = MicroRNA expression in the biology, prognosis, and therapy of Waldenström macroglobulinemia| journal = Blood| volume = 113| issue = 18| pages = 4391–4402| year = 2009| pmid = 19074725| pmc = 2943754| doi = 10.1182/blood-2008-09-178228}}</ref>
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| * increased expression of miRNAs-363*,<ref>http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000764</ref> -206,<ref>http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000490</ref> -494,<ref>http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0003134</ref> -155,<ref>http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000681</ref> -184,<ref>http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000481</ref> -542–3p.<ref>http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0003686</ref>
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| * decreased expression of miRNA-9*.<ref>http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=MI0000466</ref>
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| 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.
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| In WM-cells, [[histone deacetylase]]s and histone-modifying genes are de-regulated.<ref>{{Cite journal| last1 = Roccaro | first1 = A.| last2 = Sacco | first2 = A.| last3 = Jia | first3 = X.| last4 = Azab | first4 = A.| last5 = Maiso | first5 = P.| last6 = Ngo | first6 = H.| last7 = Azab | first7 = F.| last8 = Runnels | first8 = J.| last9 = Quang | first9 = P.| last10 = Ghobrial | first10 = I. M.| title = microRNA-dependent modulation of histone acetylation in Waldenström macroglobulinemia| journal = Blood| volume = 116| issue = 9| pages = 1506–1514| year = 2010| pmid = 20519629| pmc = 2938840| doi = 10.1182/blood-2010-01-265686}}</ref>
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| 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%).<ref>{{Cite journal| last1 = Treon | first1 = S.| last2 = Kelliher | first2 = A.| last3 = Keele | first3 = B.| last4 = Frankel | first4 = S.| last5 = Emmanouilides | first5 = C.| last6 = Kimby | first6 = E.| last7 = Schlossman | first7 = R.| last8 = Mitsiades | first8 = N.| last9 = Mitsiades | first9 = C.| last10 = Preffer | first10 = F.| last11 = Anderson | first11 = K. C.| title = Expression of serotherapy target antigens in Waldenstrom's macroglobulinemia: therapeutic applications and considerations| journal = Seminars in oncology| volume = 30| issue = 2| pages = 248–252| year = 2003| pmid = 12720146| doi = 10.1053/sonc.2003.50047}}</ref>
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| ==Associated Conditions==
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| ==Gross Pathology==
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| ==Micropathology==
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| ==References==
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| {{reflist|2}}
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| {{WH}}
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| {{WS}}
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| [[Category:Disease]]
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| [[Category:Blood]]
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| [[Category:Hematology]]
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