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

Abstract

Leukemia cells reciprocally interact with their surrounding bone marrow microenvironment (BMM), rendering it hospitable to leukemia cell survival, for instance by release of small extracellular vesicles (sEV). In converse, 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 sEV released by BMM-derived mesenchymal stromal cells (MSC). PLEKHM1-deficient MSC and their sEV carry increased amounts of syntenin and syndecan-1, resulting in a more immature B cell phenotype and increased number/function of leukemia-initiating cells (LIC) via focal adhesion kinase (FAK) and AKT signaling in B-ALL cells. Ex vivo pretreatment of LIC with sEV derived from PLEKHM1-deficient MSC led to a strong trend towards acceleration of murine and human BCR-ABL1+ B-ALL. In turn, inflammatory mediators such as recombinant or B-ALL-cell derived tumor necrosis factor (TNF) α or interleukin (IL)-1β condition murine and human MSC in vitro, decreasing PLEKHM1, while increasing syntenin and syndecan-1 in MSC, thereby perpetuating the sEV-associated circuit. Consistently, human trephine biopsies of patients with B-ALL showed a reduced percentage of PLEKHM1+ MSC. In summary, our data reveal an important role of BMM-derived sEV for driving specifically BCR-ABL1+ B-ALL, possibly contributing to its worse prognosis compared to BCR-ABL1- B-ALL, and suggest that secretion of inflammatory cytokines by cancer cells in general may similarly modulate the tumor microenvironment.

ActivinA modulates B-Acute Lymphoblastic Leukaemia cell communication and survival by inducing extracellular vesicles production

“…Increasing evidence has demonstrated a bidirectional EV-mediated crosstalk between leukemic cells and many other cell types residing within the BM niche. On the one hand, EVs released by leukemic cells have been described to induce angiogenesis 15,18 , inhibit healthy hematopoiesis 19 , modulate immune cells 20,21 and promote BM niche remodeling, for example by inducing lipolysis, to obtain growth advantage 18,22,23 . On the other hand, it has been found that the microenvironment can support the growth, survival and chemoresistance of leukemic cells through vesiculation 14,24 .…”

Extracellular vesicles in hematological malignancies: EV-dence for reshaping the tumoral microenvironment

“…Pleckstrin homology domain family M member 1 (PLEKHM1) deficiency in the bone marrow microenvironment accelerated BCR-ABL + B-ALL disease progression by altering MSC EV cargo ( 98 ). TNF-α secretion by B-ALL cells cause PLEKHM1 deficiency in MSCs that release sEVs increasing the number and improving the function of leukemia initiating cells through the transfer of enriched synthenin and syndecan-1 ( 98 ). As a result of this transfer, phosphorylation of AKT and focal adhesion kinase occurs, which in turn promotes differentiation, migration, and disease progression in BCR-ABL + B- ALL ( 98 ).…”

“…TNF-α secretion by B-ALL cells cause PLEKHM1 deficiency in MSCs that release sEVs increasing the number and improving the function of leukemia initiating cells through the transfer of enriched synthenin and syndecan-1 ( 98 ). As a result of this transfer, phosphorylation of AKT and focal adhesion kinase occurs, which in turn promotes differentiation, migration, and disease progression in BCR-ABL + B- ALL ( 98 ). The osteogenic differentiation of BM-MSCs is inhibited by miR-34a-5p carried by sEVs released by T-ALL blasts.…”

“…Interactions between Acute lymphoid leukemia (ALL) blasts and the bone marrow ME are crucial to maintain malignant cell self-renewal, expansion, and chemoresistance necessary for leukemic development (78,(94)(95)(96)(97)(98). Pleckstrin homology domain family M member 1 (PLEKHM1) deficiency in the bone marrow microenvironment accelerated BCR-ABL + B-ALL disease progression by altering MSC EV cargo (98).…”

“…Interactions between Acute lymphoid leukemia (ALL) blasts and the bone marrow ME are crucial to maintain malignant cell self-renewal, expansion, and chemoresistance necessary for leukemic development (78,(94)(95)(96)(97)(98). Pleckstrin homology domain family M member 1 (PLEKHM1) deficiency in the bone marrow microenvironment accelerated BCR-ABL + B-ALL disease progression by altering MSC EV cargo (98). TNF-a secretion by B-ALL cells cause PLEKHM1 deficiency in MSCs that release sEVs increasing the number and improving the function of leukemia initiating cells through the transfer of enriched synthenin and syndecan-1 (98).…”