TY  - JOUR
A1  - Karantanou, Christina
A1  - Minciacchi, Valentina R.
A1  - Kumar, Rahul
A1  - Zanetti, Costanza
A1  - Bravo, Jimena
A1  - Pereira, Raquel Soares
A1  - Tascher, Georg
A1  - Tertel, Tobias
A1  - Covarrubias-Pinto, Adriana
A1  - Bankov, Katrin
A1  - Pfeffermann, Lisa-Marie
A1  - Bönig, Halvard-Björn
A1  - Divieti-Pajevic, Paola
A1  - McEwan, David G.
A1  - Giebel, Bernd
A1  - Münch, Christian
A1  - Đikić, Ivan
A1  - Krause, Daniela Sandra
T1  - Impact of mesenchymal stromal cell–derived vesicular cargo on B-cell acute lymphoblastic leukemia progression
T2  - Blood Advances
N2  - Leukemia cells reciprocally interact with their surrounding bone marrow microenvironment (BMM), rendering it hospitable to leukemia cell survival, for instance through the release of small extracellular vesicles (sEVs). In contrast, we show here that BMM deficiency of pleckstrin homology domain family M member 1 (PLEKHM1), which serves as a hub between fusion and secretion of intracellular vesicles and is important for vesicular secretion in osteoclasts, accelerates murine BCR-ABL1+ B-cell acute lymphoblastic leukemia (B-ALL) via regulation of the cargo of sEVs released by BMM-derived mesenchymal stromal cells (MSCs). PLEKHM1-deficient MSCs and their sEVs carry increased amounts of syntenin and syndecan-1, resulting in a more immature B-cell phenotype and an increased number/function of leukemia-initiating cells (LICs) via focal adhesion kinase and AKT signaling in B-ALL cells. Ex vivo pretreatment of LICs with sEVs derived from PLEKHM1-deficient MSCs led to a strong trend toward acceleration of murine and human BCR-ABL1+ B-ALL. In turn, inflammatory mediators such as recombinant or B-ALL cell–derived tumor necrosis factor α or interleukin-1β condition murine and human MSCs in vitro, decreasing PLEKHM1, while increasing syntenin and syndecan-1 in MSCs, thereby perpetuating the sEV-associated circuit. Consistently, human trephine biopsies of patients with B-ALL showed a reduced percentage of PLEKHM1+ MSCs. In summary, our data reveal an important role of BMM-derived sEVs for driving specifically BCR-ABL1+ B-ALL, possibly contributing to its worse prognosis compared with BCR-ABL1− B-ALL, and suggest that secretion of inflammatory cytokines by cancer cells in general may similarly modulate the tumor microenvironment.
Y1  - 2023
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/75625
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-756253
SN  - 2473-9529
VL  - 7
IS  - 7
SP  - 1190
EP  - 1203
PB  - American Society of Hematology
CY  - Washington, DC
ER  -