Aberrant Extrafollicular B Cells, Immune Dysfunction, Myeloid Inflammation, and MyD88-Mutant Progenitors Precede Waldenstrom Macroglobulinemia.
Journal
Blood cancer discovery
ISSN: 2643-3249
Titre abrégé: Blood Cancer Discov
Pays: United States
ID NLM: 101764786
Informations de publication
Date de publication:
Nov 2021
Nov 2021
Historique:
received:
05
03
2021
revised:
07
07
2021
accepted:
24
08
2021
entrez:
15
11
2021
pubmed:
16
11
2021
medline:
16
11
2021
Statut:
epublish
Résumé
Waldenstrom macroglobulinemia (WM) and its precursor IgM gammopathy are distinct disorders characterized by clonal mature IgM-expressing B-cell outgrowth in the bone marrow. Here, we show by high-dimensional single-cell immunogenomic profiling of patient samples that these disorders originate in the setting of global B-cell compartment alterations, characterized by expansion of genomically aberrant extrafollicular B cells of the nonmalignant clonotype. Alterations in the immune microenvironment preceding malignant clonal expansion include myeloid inflammation and naïve B- and T-cell depletion. Host response to these early lesions involves clone-specific T-cell immunity that may include MYD88 mutation-specific responses. Hematopoietic progenitors carry the oncogenic MYD88 mutations characteristic of the malignant WM clone. These data support a model for WM pathogenesis wherein oncogenic alterations and signaling in progenitors, myeloid inflammation, and global alterations in extrafollicular B cells create the milieu promoting extranodal pattern of growth in differentiated malignant cells. These data provide evidence that growth of the malignant clone in WM is preceded by expansion of extrafollicular B cells, myeloid inflammation, and immune dysfunction in the preneoplastic phase. These changes may be related in part to MYD88 oncogenic signaling in pre-B progenitor cells and suggest a novel model for WM pathogenesis.
Identifiants
pubmed: 34778800
doi: 10.1158/2643-3230.BCD-21-0043
pii: 2643-3230.BCD-21-0043
pmc: PMC8580616
doi:
Substances chimiques
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
Pagination
600-615Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008169
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR077926
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197603
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA238471
Pays : United States
Informations de copyright
©2021 American Association for Cancer Research.
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