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ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment (CRISPR Screen)

ABSTRACT: Immunomodulatory drugs (IMiDs) have markedly improved patient outcome in multiple myeloma (MM); however, resistance to IMiDs commonly underlies relapse of disease. Here we identify and validate that TNF receptor associated factor protein family TRAF2 KD/KO in MM cells mediates IMiDs resistance via activation of non-canonical NF-kB and MEK-ERK signaling. Within MM bone marrow (BM) stromal cell supernatants, TNF-a induces proteasomal degradation of TRAF2, non-canonical NF-kB, and downstream ERK signaling in MM cells, whereas IL-6 directly triggers ERK activation. RNA sequencing of MM patient samples shows nearly universal ERK pathway activation at relapse on lenalidomide maintenance therapy, confirming its clinical relevance. Combination MEK inhibitor treatment restores IMiDs sensitivity of TRAF2 KO cells both in vitro and in vivo using an inducible TRAF2 KD MM xenograft model. Our studies provide the framework for clinical trials of MEK inhibitors to overcome IMiDs resistance in the BM microenvironment and improve patient outcome in MM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171339 | GEO | 2021/06/15

REPOSITORIES: GEO

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Project description:A rare complication of multiple myeloma is a secondary extramedullary involvement, and the skin is one of the possible sites, due to the physiological homing of plasma cells (PCs) into the skin. The article reports a case of a relapsed refractory MM patient, who developed a cutaneous localization after 16 months from the diagnosis under Bortezomib treatment without a leukemic phase. Patient was refractory to Bortezomib. We analyzed the gene expression profiles, the immunophenotypic and immunohistochemistry profiles of MM cells across the course of the disease at the bone marrow and skin localization. Data obtained were further expanded by an immunohistochemistry analysis on selected molecules in a large cohort of MM patients with cutaneous localization. In particular we focused on the expression of chemokines and chemokine receptors involved in the PC skin homing. The mechanisms behind the extramedullary spread and the formation of localizations outside the BM are not completely understood. Several studies investigated the expression profile of myeloma cells in the extramedullary localization by immunohistochemistry without a prospective molecular and immunohistochemistry study across the progression of the disease and consequently the development of extramedullary localization. This case indicates that the skin homing of MM cells could be related to the high CCR10 expression of at the diagnosis and relapse and the loss of CXCR4 surface expression across the progression of the disease in the contest of Bortezomib resistance. This data was further confirmed in a larger series of patients. Moreover, high expression of CD44, together with the down-regulation of CD54 and the lack of expression of CD56 by MM cells in the BM relapse with the re-acquisition of both antigens during the cutaneous relapse may be the mechanism that drives the escape from BM of PCs and their localization into the skin. Our data have identified a possible mechanism that drives the escape from BM of myeloma cells and their localization into the skin.

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ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment (CRISPR Screen)

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