Acute lymphoblastic leukemia cells create a leukemic niche without affecting the CXCR4/CXCL12 axis

Rooij, Bob de; Polak, Roel; Berk, Lieke C. J. van den; Stalpers, Femke; Pieters, Rob; Boer, Monique L. den

doi:10.3324/haematol.2016.159517

Cited by 22 publications

(29 citation statements)

References 14 publications

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“…vivo co-cultures of primary mesenchymal stromal cells and either the Nalm6 cell line or primary ALL cells that although the CXCL12/CXCR4 axis was involved in leukemic cell migration, other chemokines, such as C-C motif chemokine ligand 2 (CCL2) and CXCL8 may be involved in leukemic niche formation, independently of the CXCL12/CXCR4 axis.Transwell assays also demonstrated that leukemic cells could recruit mesenchymal stromal cells to initiate the leukemic niche, in which secreted chemokines might attract other leukemic cells while inhibiting that of healthy hematopoietic progenitors and mesenchymal stromal cells[201]. These results are consistent with those of other studies including that of Colmone et al in which Nalm6 cells colonized CXCL12 niches in the BM of xenografted mice, which subsequently resulted in marked downregulation[43,202].…”

supporting

confidence: 89%

Mechanisms of extramedullary relapse in acute lymphoblastic leukemia: Reconciling biological concepts and clinical issues

et al. 2019

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Long-term survival rates in childhood acute lymphoblastic leukemia (ALL) are currently above 85% due to huge improvements in treatment. However, 15-20% of children still experience relapses. Relapses can either occur in the bone marrow or at extramedullary sites, such as gonads or the central nervous system (CNS), formerly referred to as ALL-blast sanctuaries. The reason why ALL cells migrate to and stay in these sites is still unclear. In this review, we have attempted to assemble the evidence concerning the microenvironmental factors that could explain why ALL cells reside in such sites. We present criteria that make extramedullary leukemia niches and solid tumor metastatic niches comparable. Indeed, considering extramedullary leukemias as metastases could be a useful approach for proposing more effective treatments. In this context, we conclude with several examples of potential niche-based therapies which could be successfully added to current treatments of ALL.

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confidence: 89%

Mechanisms of extramedullary relapse in acute lymphoblastic leukemia: Reconciling biological concepts and clinical issues

et al. 2019

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“…CXCR2 primarily mediates neutrophil migration to sites of inflammation (Richardson et al, 2003); in addition, it represents a selective migratory pathway for BCP-ALL blasts toward the leukemic niche (De Rooij et al, 2017). Since we previously showed that E/R altered cell migration (Palmi et al, 2014) E/R + =30Á2 AE 9Á1; ctr = 14Á3 AE 9Á6, P < 0Á01).…”

Section: The Inflamed Mesenchymal Niche Preferentially Attracts E/r + B-progenitors Through the Cxcr2 Receptormentioning

confidence: 96%

“…Of note, we have previously suggested that may affect pre-leukemic cells interactions with the BM stroma by altering their adhesive and migratory properties (Palmi et al, 2014). In addition to function as important modulators of inflammation (Bernardo & Fibbe, 2013), BM-mesenchymal stromal cells (MSC) have gained great interest for their active role in leukemia pathogenesis (Lo et al, 2014;Polak et al, 2015;Naderi et al, 2015;De Rooij et al, 2017). In particular, it has been shown that BM-MSC alterations are able to induce genotoxic stress in HSPC leading to hematological malignancies (Raaijmakers et al, 2010;Zambetti et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Pro‐inflammatory cytokines favor the emergence of ETV6‐RUNX1‐positive pre‐leukemic cells in a model of mesenchymal niche

et al. 2020

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ETV6-RUNX1 (E/R) fusion gene, arising in utero from translocation t(12;21)(p13:q22), is the most frequent alteration in childhood acute lymphoblastic leukemia (ALL). However, E/R is insufficient to cause overt leukemia since it generates a clinically silent pre-leukemic clone which persists in the bone marrow but fails to out-compete normal progenitors. Conversely, pre-leukemic cells show increased susceptibility to transformation following additional genetic insults. Infections/inflammation are the most accredited triggers for mutations accumulation and leukemic transformation in E/R + pre-leukemic cells. However, precisely how E/R and inflammation interact in promoting leukemia is still poorly understood. Here we demonstrate that IL6/TNFa/ILb pro-inflammatory cytokines cooperate with BM-MSC in promoting the emergence of E/R + Ba/F3 over their normal counterparts by differentially affecting their proliferation and survival. Moreover, IL6/TNFa/ILb-stimulated BM-MSC strongly attract E/R + Ba/F3 in a CXCR2-dependent manner. Interestingly, E/R-expressing human CD34 + IL7R + progenitors, a putative population for leukemia initiation during development, were preserved in the presence of BM-MSC and IL6/ TNFa/ILb compared to their normal counterparts. Finally, the extent of DNA damage increases within the inflamed niche in both control and E/Rexpressing Ba/F3, potentially leading to transformation in the apoptosis-resistant pre-leukemic clone. Overall, our data provide new mechanistic insights into childhood ALL pathogenesis.

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“…These alterations are not restricted to malignancies in myeloid lineage. Ex vivo coculture model has indicated that acute lymphoblastic leukaemia cells can create a leukaemic niche in the direction of attracting leukaemic cells and repelling normal haematopoietic cells 7 . BM‐MSCs from multiple myeloma (MM) patients also show much lower proliferative activity and different gene expression compared with normal BM‐MSCs 8 .…”

Section: Introductionmentioning

confidence: 99%

Common and different alterations of bone marrow mesenchymal stromal cells in myelodysplastic syndrome and multiple myeloma

et al. 2020

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Objective:The objective of this study was to explore characteristics of bone marrow mesenchymal stromal cells (BM-MSCs) derived from patients with myelodysplastic syndrome (MDS) and multiple myeloma (MM). Methods: BM-MSCs were recovered from 17 of MDS patients, 23 of MM patients and 9 healthy donors and were passaged until proliferation stopped. General characteristics and gene expression profiles of MSCs were analysed. In vitro, ex vivo coculture, immunohistochemistry and knockdown experiments were performed to verify gene expression changes. Results: BM-MSCs failed to culture in 35.0% of patients and 50.0% of recovered BM-MSCs stopped to proliferate before passage 6. MDS-and MM-MSCs shared characteristics including decreased osteogenesis, increased angiogenesis and senescence-associated molecular pathways. In vitro and ex vivo experiments showed disease-specific changes such as neurogenic tendency in MDS-MSCs and cardiomyogenic tendency in MM-MSCs. Although the age of normal control was younger than patients and telomere length was shorter in patient's BM-MSCs, they were not different according to disease category nor degree of proliferation. Specifically, poorly proliferation BM-MSCs showed CDKN2A overexpression and CXCL12 downregulation. Immunohistochemistry of BM biopsy demonstrated that CDKN2A was intensely accumulation in perivascular BM-MSCs failed to culture. Interestingly, patient's BM-MSCs revealed improved proliferation activity after CDKN2A knockdown. Conclusion: These results collectively indicate that MDS-MSCs and MM-MSCs have common and different alterations at various degrees. Hence, it is necessary to evaluate their alteration status using representative markers such as CDKN2A expression.

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Acute lymphoblastic leukemia cells create a leukemic niche without affecting the CXCR4/CXCL12 axis

Abstract: BdR and RP contributed equally to this work.

Cited by 22 publications

References 14 publications

Mechanisms of extramedullary relapse in acute lymphoblastic leukemia: Reconciling biological concepts and clinical issues

Mechanisms of extramedullary relapse in acute lymphoblastic leukemia: Reconciling biological concepts and clinical issues

Pro‐inflammatory cytokines favor the emergence of ETV6‐RUNX1‐positive pre‐leukemic cells in a model of mesenchymal niche

Common and different alterations of bone marrow mesenchymal stromal cells in myelodysplastic syndrome and multiple myeloma

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