Impact of mesenchymal stromal cell–derived vesicular cargo on B-cell acute lymphoblastic leukemia progression

  • 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.

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Author:Christina KarantanouORCiDGND, Valentina R. MinciacchiORCiD, Rahul KumarORCiD, Costanza ZanettiORCiDGND, Jimena Bravo, Raquel Soares PereiraGND, Georg TascherORCiDGND, Tobias TertelORCiDGND, Adriana Covarrubias-PintoORCiD, Katrin BankovORCiDGND, Lisa-Marie PfeffermannGND, Halvard-Björn BönigORCiDGND, Paola Divieti-PajevicORCiD, David G. McEwanORCiD, Bernd GiebelORCiDGND, Christian MünchORCiD, Ivan ĐikićORCiDGND, Daniela Sandra KrauseORCiDGND
Pubmed Id:
Parent Title (English):Blood Advances
Publisher:American Society of Hematology
Place of publication:Washington, DC
Document Type:Article
Date of Publication (online):2023/03/31
Date of first Publication:2023/03/31
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2023/09/13
Page Number:14
First Page:1190
Last Page:1203
Fachübergreifende Einrichtungen / Buchmann Institut für Molekulare Lebenswissenschaften (BMLS)
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International