Universität zu Köln

Pindzola, Grace M., Razzaghi, Raud ORCID: 0000-0002-6410-9932, Tavory, Rachel N., Nguyen, Hang T., Morris, Vivian M., Li, Moyi, Agarwal, Shreya, Huang, Bonnie, Okada, Takaharu, Reinhardt, Hans C., Knittel, Gero, Kashkar, Hamid, Young, Ryan M., Pittaluga, Stefania and Muppidi, Jagan R. (2022). Aberrant expansion of spontaneous splenic germinal centers induced by hallmark genetic lesions of aggressive lymphoma. Blood, 140 (10). S. 1119 - 1132. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 1528-0020

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Abstract

Unique molecular vulnerabilities have been identified in the aggressive MCD/C5 genetic subclass of diffuse large B-cell lymphoma (DLBCL). However, the premalignant cell-of-origin exhibiting MCD-like dependencies remains elusive. In this study, we examined animals carrying up to 4 hallmark genetic lesions found in MCD consisting of gain-of-function mutations in Myd88 and Cd79b, loss of Prdm1, and overexpression of BCL2. We discovered that expression of combinations of these alleles in vivo promoted a cell-intrinsic accumulation of B cells in spontaneous splenic germinal centers (GCs). As with MCD, these premalignant B cells were enriched for B-cell receptors (BCRs) with evidence of self-reactivity, displayed a de novo dependence on Tlr9, and were more sensitive to inhibition of Bruton's tyrosine kinase. Mutant spontaneous splenic GC B cells (GCB) showed increased proliferation and IRF4 expression. Mice carrying all 4 genetic lesions showed a >50-fold expansion of spontaneous splenic GCs exhibiting aberrant histologic features with a dark zone immunophenotype and went on to develop DLBCL in the spleen with age. Thus, by combining multiple hallmark genetic alterations associated with MCD, our study identifies aberrant spontaneous splenic GCBs as a likely cell-of-origin for this aggressive genetic subtype of lymphoma.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pindzola, Grace M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Razzaghi, Raud UNSPECIFIED orcid.org/0000-0002-6410-9932 UNSPECIFIED Tavory, Rachel N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nguyen, Hang T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Morris, Vivian M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Moyi UNSPECIFIED UNSPECIFIED UNSPECIFIED Agarwal, Shreya UNSPECIFIED UNSPECIFIED UNSPECIFIED Huang, Bonnie UNSPECIFIED UNSPECIFIED UNSPECIFIED Okada, Takaharu UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinhardt, Hans C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Knittel, Gero UNSPECIFIED UNSPECIFIED UNSPECIFIED Kashkar, Hamid UNSPECIFIED UNSPECIFIED UNSPECIFIED Young, Ryan M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pittaluga, Stefania UNSPECIFIED UNSPECIFIED UNSPECIFIED Muppidi, Jagan R. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-688832
DOI:	10.1182/blood.2022015926
Journal or Publication Title:	Blood
Volume:	140
Number:	10
Page Range:	S. 1119 - 1132
Date:	2022
Publisher:	AMER SOC HEMATOLOGY
Place of Publication:	WASHINGTON
ISSN:	1528-0020
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PLASMA-CELL DIFFERENTIATION; IFN-GAMMA RECEPTOR; B-CELLS; MYD88(L265P); PATHOGENESIS; EXPRESSION; MUTATIONS; SURVIVAL; ANTIGEN; BLIMP1 Multiple languages Hematology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68883