Human MYD88L265P is insufficient by itself to drive neoplastic transformation in mature mouse B cells.
Alleles
Amino Acid Substitution
Animals
B-Lymphocytes
/ metabolism
Biomarkers, Tumor
Biopsy
Cell Transformation, Neoplastic
/ genetics
Disease Models, Animal
Gene Expression
Genetic Association Studies
Genetic Predisposition to Disease
Humans
Immunohistochemistry
Immunophenotyping
Mice
Mice, Transgenic
Mutation
Myeloid Differentiation Factor 88
/ genetics
Neoplasm Grading
Transcriptome
Waldenstrom Macroglobulinemia
/ etiology
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
12 11 2019
12 11 2019
Historique:
received:
18
06
2019
accepted:
20
08
2019
entrez:
8
11
2019
pubmed:
8
11
2019
medline:
2
9
2020
Statut:
ppublish
Résumé
MYD88 L265P is the most common mutation in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) and one of the most frequent in poor-prognosis subtypes of diffuse large B-cell lymphoma (DLBCL). Although inhibition of the mutated MYD88 pathway has an adverse impact on LPL/WM and DLBCL cell survival, its role in lymphoma initiation remains to be clarified. We show that in mice, human MYD88L265P promotes development of a non-clonal, low-grade B-cell lymphoproliferative disorder with several clinicopathologic features that resemble human LPL/WM, including expansion of lymphoplasmacytoid cells, increased serum immunoglobulin M (IgM) concentration, rouleaux formation, increased number of mast cells in the bone marrow, and proinflammatory signaling that progresses sporadically to clonal, high-grade DLBCL. Murine findings regarding differences in the pattern of MYD88 staining and immune infiltrates in the bone marrows of MYD88 wild-type (MYD88WT) and MYD88L265P mice are recapitulated in the human setting, which provides insight into LPL/WM pathogenesis. Furthermore, histologic transformation to DLBCL is associated with acquisition of secondary genetic lesions frequently seen in de novo human DLBCL as well as LPL/WM-transformed cases. These findings indicate that, although the MYD88L265P mutation might be indispensable for the LPL/WM phenotype, it is insufficient by itself to drive malignant transformation in B cells and relies on other, potentially targetable cooperating genetic events for full development of lymphoma.
Identifiants
pubmed: 31698464
pii: 422699
doi: 10.1182/bloodadvances.2019000588
pmc: PMC6855113
doi:
Substances chimiques
Biomarkers, Tumor
0
MYD88 protein, human
0
Myeloid Differentiation Factor 88
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3360-3374Subventions
Organisme : NCI NIH HHS
ID : R01 CA196783
Pays : United States
Informations de copyright
© 2019 by The American Society of Hematology.
Références
Leukemia. 2013 Aug;27(8):1722-8
pubmed: 23446312
Nat Med. 2018 May;24(5):679-690
pubmed: 29713087
Leukemia. 2016 May;30(5):1116-25
pubmed: 26867669
J Immunol. 2002 Jan 15;168(2):744-54
pubmed: 11777968
Br J Haematol. 2017 Nov;179(3):439-448
pubmed: 28770576
Blood Cancer J. 2016 Nov 4;6(11):e488
pubmed: 27813533
Blood. 2014 Mar 13;123(11):1637-46
pubmed: 24366360
J Biol Chem. 1998 May 15;273(20):12203-9
pubmed: 9575168
Nat Rev Rheumatol. 2016 Apr;12(4):198-200
pubmed: 27006311
N Engl J Med. 2015 Apr 9;372(15):1430-40
pubmed: 25853747
Nature. 2000 Feb 3;403(6769):503-11
pubmed: 10676951
Genesis. 2006 Jan;44(1):23-8
pubmed: 16400644
Leuk Lymphoma. 2015 Apr;56(4):1179-80
pubmed: 25030038
Haematologica. 2017 Nov;102(11):e452-e455
pubmed: 28798070
Am J Hematol. 2015 Aug;90(8):696-701
pubmed: 25963924
Blood. 2006 Jun 1;107(11):4205
pubmed: 16739263
Nature. 2018 Aug;560(7718):387-391
pubmed: 29925955
Blood. 2016 Aug 11;128(6):827-38
pubmed: 27301862
Blood. 2002 Jul 1;100(1):246-58
pubmed: 12070034
N Engl J Med. 2018 Apr 12;378(15):1396-1407
pubmed: 29641966
PLoS One. 2013 Jul 08;8(7):e69208
pubmed: 23861962
Am J Hematol. 2016 Oct;91(10):1032-5
pubmed: 27415417
J Thorac Oncol. 2017 Aug;12(8):1268-1279
pubmed: 28483607
Blood. 2013 May 30;121(22):4504-11
pubmed: 23532735
Cold Spring Harb Perspect Biol. 2014 Sep 04;6(10):a016295
pubmed: 25190079
Cancer Res. 2018 May 15;78(10):2457-2462
pubmed: 29703722
Blood. 2014 Dec 18;124(26):3896-904
pubmed: 25359991
Sci Signal. 2016 Aug 23;9(442):ra85
pubmed: 27555662
Cell Death Differ. 2010 Apr;17(4):689-98
pubmed: 19911008
Cancer Cell. 2006 May;9(5):379-90
pubmed: 16697958
Nat Med. 2015 Oct;21(10):1190-8
pubmed: 26366712
Blood. 2010 Apr 29;115(17):3580-8
pubmed: 20190191
Br J Haematol. 2018 Feb;180(3):374-380
pubmed: 29181840
Cell. 2008 Dec 12;135(6):1028-38
pubmed: 19070574
Nat Med. 2015 Aug;21(8):922-6
pubmed: 26193343
Haematologica. 2018 Sep;103(9):e408-e411
pubmed: 29599202
Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):5735-9
pubmed: 22451912
J Allergy Clin Immunol. 2018 May;141(5):1943-1947.e9
pubmed: 29427642
Nature. 2011 Feb 3;470(7332):115-9
pubmed: 21179087
N Engl J Med. 2012 Aug 30;367(9):826-33
pubmed: 22931316
J Exp Med. 2014 Mar 10;211(3):413-26
pubmed: 24534189
Cell. 2017 Oct 5;171(2):481-494.e15
pubmed: 28985567
Blood Cancer J. 2015 May 15;5:e314
pubmed: 25978434
Blood. 2013 Mar 28;121(13):2522-8
pubmed: 23355535
Blood Cancer J. 2017 Aug 25;7(8):e591
pubmed: 28841204
Blood. 2013 Aug 15;122(7):1222-32
pubmed: 23836557
Blood. 2011 Nov 17;118(20):5540-9
pubmed: 21921047
Blood. 2016 Feb 18;127(7):869-81
pubmed: 26702065
J Immunol. 2015 Sep 15;195(6):2908-16
pubmed: 26238488
Oncotarget. 2016 Sep 27;7(39):63362-63373
pubmed: 27556513
J Natl Cancer Inst. 2010 Apr 21;102(8):557-67
pubmed: 20181958
Blood. 2016 Jun 2;127(22):2732-41
pubmed: 27048211