Bone marrow niches in myeloid neoplasms

Kitagawa, Masanobu; Kurata, Morito; Onishi, Iichiroh; Yamamoto, Kouhei

doi:10.1111/pin.12870

Cited by 5 publications

(6 citation statements)

References 45 publications

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“…The CXCL12 chemokine is constitutively released from bone marrow stromal cells and contributes to maintaining stem cells in bone marrow niches by binding to CXCR4 on CD34+/CD117 + hemopoietic progenitors and leukemic blasts too [ 16 ]. Therefore, CXCL12 may also be involved in protecting the leukemic stem cells and contributing to myelofibrosis progression [ 22 ], though CXCR4 is downregulated in the malignant progenitors, which may explain extramedullary clonal hematopoiesis in myelofibrosis [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, CXCL12 may also be involved in protecting the leukemic stem cells and contributing to myelofibrosis progression [ 22 ], though CXCR4 is downregulated in the malignant progenitors, which may explain extramedullary clonal hematopoiesis in myelofibrosis [ 41 ]. Endothelial cells may also express CXCL12, although at a lower level [ 16 ]. CXCL12 plays an essential role in stem cell homing at transplantation and the CXCL12/CXCR4 interaction supports stromal cell resistance and restoration of the stromal network after myeloablative irradiation [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…The chemokine CXCL12 (stromal cell-derived factor 1 - SDF1, or C-X-C motif chemokine 12) produced by stromal and endothelial cells and osteoblasts, plays an important role in maintaining stem cell quiescence by safeguarding both the perivascular or endosteal bone marrow niches [ 16 ]. Its receptor CXCR4 is known to be expressed in CD34+/c-kit + hemopoetic progenitors and leukemic blasts.…”

Section: Introductionmentioning

confidence: 99%

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Correlations Between the Expression of Stromal Cell Activation Related Biomarkers, L-NGFR, Phospho-ERK1-2 and CXCL12, and Primary Myelofibrosis Progression

Szèkely

Krenács

Maros

et al. 2022

Pathol. Oncol. Res.

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In myelofibrosis, pathologically enhanced extracellular matrix production due to aberrant cytokine signalling and clonal megakaryocyte functions result(s) in impaired hemopoiesis. Disease progression is still determined by detecting reticulin and collagen fibrosis with Gomori’s silver impregnation. Here, we tested whether the expression growth related biomarkers L-NGFR/CD271, phospho-ERK1-2 and CXCL12 can be linked to the functional activation of bone marrow stromal cells during primary myelofibrosis progression. Immunoscores for all tested biomarkers showed varying strength of positive statistical correlation with the silver impregnation based myelofibrosis grades. The intimate relationship between spindle shaped stromal cells positive for all three markers and aberrant megakaryocytes was likely to reflect their functional cooperation. L-NGFR reaction was restricted to bone marrow stromal cells and revealed the whole length of their processes. Also, L-NGFR positive cells showed the most intersections, the best statistical correlations with myelofibrosis grades and the strongest interrater agreements. CXCL12 reaction highlighted stromal cell bodies and a weak extracellular staining in line with its constitutive release. Phospho-ERK1-2 reaction showed a similar pattern to CXCL12 in stromal cells with an additional nuclear staining in agreement with its role as a transcription factor. Both p-ERK1-2 and CXCL12 were also expressed at a moderate level in sinus endothelial cells. Connexin 43 gap junction communication channels, known to be required for CXCL12 release to maintain stem cell niche, were also expressed progressively in the myelofibrotic stromal network as a support of compartmental functions. Our results suggest that, diverse growth related pathways are activated in the functionally coupled bone marrow stromal cells during myelofibrosis progression. L-NGFR expression can be a useful biological marker of stromal cell activation which deserves diagnostic consideration for complementing Gomori’s silver impregnation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Correlations Between the Expression of Stromal Cell Activation Related Biomarkers, L-NGFR, Phospho-ERK1-2 and CXCL12, and Primary Myelofibrosis Progression

Szèkely

Krenács

Maros

et al. 2022

Pathol. Oncol. Res.

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“…MDS is myeloid neoplasms characterized by clonal proliferation of hematopoietic stem cells, recurrent genetic abnormalities, ineffective hematopoiesis, peripheral-blood cytopenia, and a high risk of evolution to AML (1). Recent evidence has revealed that the bone marrow microenvironment (BMME), including mesenchymal stem cells and hematopoietic stem cell niche cells, is another key contributor to disease initiation and progression (2). Malignant clonal cells can modify the BMME via aberrant production of secreted factors, and the resulting dysfunctional BMME further promotes clonal expansion (3,4).…”

Section: Introductionmentioning

confidence: 99%

Clonal MDS/AML cells with enhanced TWIST1 expression reprogram the differentiation of bone marrow MSCs

Li¹,

Li²,

Wang³

et al. 2023

Preprint

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Bone marrow-derived mesenchymal stem cells (BMMSCs) have the ability to differentiate into osteoblasts and adipocytes, and have been found to promote disease progression of myeloid malignancies like myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). MDS/AML patient-derived BMMSCs often show a shift in the balance between osteoblastogenesis and adipogenesis, indicating that BMMSCs may be reprogrammed or educated. However, the results of reprogrammed differentiation have been inconclusive. In this study, we found that clonal MDS/AML cells promote adipogenic differentiation and inhibit osteogenic differentiation of BMMSCs, which in turn promotes MDS expansion. Mechanistically, highly expressed transcription factor TWIST1 in clonal MDS/AML cells plays a vital role in the MDS/AML cell-mediated BMMSCs reprogramming differentiation. Enhanced TWIST1 expression induces MDS/AML cells to secrete more IFN-γ, which can induce oxidative stress through STAT1-depenent manner, ultimately causing enhanced adipogenic differentiation and inhibited osteogenic differentiation in BMMSCs. Overall, our findings suggest that targeting the driving oncogenes in malignant clonal cells, such as TWIST1, may offer new therapeutic strategies by remodeling the surrounding bone marrow microenvironment in the treatment of MDS/AML and other hematopoietic malignancies.

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“…The bone marrow niche is defined as a local tissue microenvironment that maintains and regulates hematopoietic stem cells (HSCs). Many previous studies have suggested that mesenchymal stem cells (MSCs) and vascular endothelial cells maintain HSCs and regulate their proliferation and differentiation in the bone marrow niche [ 1 , 2 , 3 , 4 ]. The bone marrow niche has been rapidly elucidated in recent years by next-generation sequencing and cell analysis techniques [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of the Factor That Leads Human Mesenchymal Stem Cell Lines into Decellularized Bone

et al. 2022

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Hematopoiesis is maintained by the interaction of hematopoietic stem cells (HSCs) and bone marrow mesenchymal stem cells (MSCs) in bone marrow microenvironments, called niches. Certain genetic mutations in MSCs, not HSCs, provoke some hematopoietic neoplasms, such as myelodysplastic syndrome. An in vivo bone marrow niche model using human MSC cell lines with specific genetic mutations and bone scaffolds is necessary to elucidate these interactions and the disease onset. We focused on decellularized bone (DCB) as a useful bone scaffold and attempted to induce human MSCs (UE7T-9 cells) into the DCB. Using the CRISPR activation library, we identified SHC4 upregulation as a candidate factor, with the SHC4 overexpression in UE7T-9 cells activating their migratory ability and upregulating genes to promote hematopoietic cell migration. This is the first study to apply the CRISPR library to engraft cells into decellularized biomaterials. SHC4 overexpression is essential for engrafting UE7T-9 cells into DCB, and it might be the first step toward creating an in vivo human–mouse hybrid bone marrow niche model.

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Bone marrow niches in myeloid neoplasms

Cited by 5 publications

References 45 publications

Correlations Between the Expression of Stromal Cell Activation Related Biomarkers, L-NGFR, Phospho-ERK1-2 and CXCL12, and Primary Myelofibrosis Progression

Correlations Between the Expression of Stromal Cell Activation Related Biomarkers, L-NGFR, Phospho-ERK1-2 and CXCL12, and Primary Myelofibrosis Progression

Clonal MDS/AML cells with enhanced TWIST1 expression reprogram the differentiation of bone marrow MSCs

Identification of the Factor That Leads Human Mesenchymal Stem Cell Lines into Decellularized Bone

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