Role of the microenvironment in myeloid malignancies

Hepatocyte growth factor (HGF)/c‐met pathway activation has been implicated in the pathogenesis of multiple myeloma (MM), and blocking this pathway has been considered a rational therapeutic strategy for treating MM. Aptamers are single‐stranded nucleic acid molecules that fold into complex 3D structures and bind to a variety of targets. Recently, it was reported that DNA aptamer SL1 exhibited high specificity and affinity for c‐met and inhibited HGF/c‐met signaling in SNU‐5 cells. However, as the first c‐met‐targeted DNA aptamer to be identified, application of SL1 to myeloma treatment requires further investigation. Here, we explore the potential application of SL1 in MM. Our results indicated that c‐met expression is gradually increased in MM patients and contributes to poor outcomes. SL1 selectively bound to c‐met‐positive MM cells but not to normal B cells and suppressed the growth, migration and adhesion of MM cells in vitro in a co‐culture model performed with HS5 cells, wherein SL1 inhibited HGF‐induced activation of c‐met signaling. In vivo and ex vivo fluorescence imaging showed that SL1 accumulated in the c‐met positive tumour areas. In addition, SL1 was active against CD138+ primary MM cells and displayed a synergistic inhibition effect with bortezomib. Collectively, our data suggested that SL1 could be beneficial as a c‐met targeted antagonist in MM.

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“…(BMME) and the signaling that results. 4 One promising candidate signaling pathway is the hepatocyte growth factor (HGF)/c-met pathway.…”

Section: Most Of MM Development Depends On the Interactions Between Mmentioning

confidence: 99%

“…Most of MM development depends on the interactions between MM cells and components of the bone marrow microenvironment (BMME) and the signaling that results . One promising candidate signaling pathway is the hepatocyte growth factor (HGF)/c‐met pathway.…”

Section: Introductionmentioning

confidence: 99%

Targeting c‐met receptor tyrosine kinase by the DNA aptamer SL1 as a potential novel therapeutic option for myeloma

Zhang

Gao

Zhou

et al. 2018

J Cellular Molecular Medi

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“…These cells represent 0.3% of BM nucleated cells and generate the CD146 + cells/pericytes and nestin + cells that are located in the perivascular niche (2). These cells represent 0.3% of BM nucleated cells and generate the CD146 + cells/pericytes and nestin + cells that are located in the perivascular niche (2).…”

Section: Stromal Cellular Componentsmentioning

confidence: 99%

“…The most immature precursors of all other stromal cells are the LepR + cells, which are quiescent but proliferate under stress. These cells represent 0.3% of BM nucleated cells and generate the CD146 + cells/pericytes and nestin + cells that are located in the perivascular niche (2).…”

Section: Stromal Cellular Componentsmentioning

confidence: 99%

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Evaluation of bone marrow microenvironment could change how myelodysplastic syndromes are diagnosed and treated

Aanei

Catafal

2018

Cytometry Pt A

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Myelodysplastic syndromes are a heterogeneous group of clonal hematopoietic disorders. However, the therapies used against the hematopoietic stem cells clones have limited efficacy; they slow the evolution toward acute myeloid leukemia rather than stop clonal evolution and eradicate the disease. The progress made in recent years regarding the role of the bone marrow microenvironment in disease evolution may contribute to progress in this area. This review presents the recent updates on the role of the bone marrow microenvironment in myelodysplastic syndromes pathogenesis and tries to find answers regarding how this information could improve myelodysplastic syndromes diagnosis and therapy.

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Y‐box binding protein 1 in small extracellular vesicles reduces mesenchymal stem cell differentiation to osteoblasts—implications for acute myeloid leukaemia

Chetty,

Ghanam,

Lichá

et al. 2024

J of Extracellular Vesicle

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Small extracellular vesicles (sEVs) released by acute myeloid leukaemia (AML) cells have been reported to influence the trilineage differentiation of bone marrow‐derived mesenchymal stem cells (BM‐MSCs). However, it remains elusive which biological cargo from AML‐sEVs is responsible for this effect. In this study, sEVs were isolated from cell‐conditioned media and blood plasma using size‐exclusion chromatography and ultrafiltration and characterized according to MISEV2018 guidelines. Our results demonstrated that AML‐sEVs increased the proliferation of BM‐MSCs. Conversely, key proteins that are important for normal haematopoiesis were downregulated in BM‐MSCs. Additionally, we revealed that AML‐sEVs significantly reduced the differentiation of BM‐MSCs to osteoblasts without affecting adipogenic or chondrogenic differentiation. Next, LC‐MS/MS proteomics elucidated that various proteins, including Y‐box‐binding protein 1 (YBX1), were upregulated in both AML‐sEVs and BM‐MSCs treated with AML‐sEVs. Clinically relevant, we found that YBX1 is considerably upregulated in most paediatric AML patient‐derived sEVs compared to healthy controls. Interestingly, sEVs isolated after the downregulation of YBX1 in AML cells remarkably rescued the osteoblastic differentiation of BM‐MSCs. Altogether, our data demonstrate for the first time that YBX1 containing AML‐sEVs is one of the key players that disrupt the normal function of bone marrow microenvironment by reducing the osteogenic differentiation of BM‐MSCs.

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Role of the microenvironment in myeloid malignancies

Cited by 34 publications

References 150 publications

Targeting c‐met receptor tyrosine kinase by the DNA aptamer SL1 as a potential novel therapeutic option for myeloma

Targeting c‐met receptor tyrosine kinase by the DNA aptamer SL1 as a potential novel therapeutic option for myeloma

Evaluation of bone marrow microenvironment could change how myelodysplastic syndromes are diagnosed and treated

Y‐box binding protein 1 in small extracellular vesicles reduces mesenchymal stem cell differentiation to osteoblasts—implications for acute myeloid leukaemia

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