Diverging impact of cell fate determinants Scrib and Llgl1 on adhesion and migration of hematopoietic stem cells

Dash, Banaja P; Schnöder, Tina M.; Kathner, Carolin; Mohr, Juliane; Weinert, Sönke; Herzog, Carolin; Godavarthy, Parimala Sonika; Zanetti, Costanza; Perner, Florian; Braun-Dullaeus, Rüdiger C.; Hartleben, Björn; Huber, Tobias B.; Walz, Gerd; Naumann, Michael; Ellis, Sarah; Vasioukhin, Valera; Kähne, Thilo; Krause, Daniela; Heidel, Florian H.

doi:10.1007/s00432-018-2724-3

Cited by 5 publications

(4 citation statements)

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“…While steady state hematopoiesis was not affected, serial transplantation and application of cell stress resulted in impaired HSC function. In a second report, the authors provided evidence that Scrib-deficient hematopoietic stem-and progenitor cells (HSPCs) fail in proper adhesion and have decreased migratory capacity [10], effects that were not detected in HSPCs after inactivation of Llgl1. With regards to malignant transformation, deletion of Scrib impaired the development of AML in vivo and this negative effect on LSC function was underlined by selection of partially and non-excised clones in secondary recipient hosts.…”

Section: Influence Of Scribble Polarity Complex On Hematopoiesis and mentioning

confidence: 99%

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2018

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Section: Influence Of Scribble Polarity Complex On Hematopoiesis and mentioning

confidence: 99%

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2018

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“…Numerous prior efforts have used co-immunopreciptitation with mass spectrometry (IP-MS) to identify binding partners for Dlg, Scrib, and Lgl (Audebert et al, 2004;Van Campenhout et al, 2011;Anastas et al, 2012;Belotti et al, 2013;Michaelis et al, 2013;Nagasaka et al, 2013;Ivarsson et al, 2014;Waaijers et al, 2016;Drew et al, 2017;Dash et al, 2018;Portela et al, 2018;Nakajima et al, 2019) (reviewed in (Stephens et al, 2018)). However, such experiments have yielded largely non-overlapping lists of binding partners and relatively few mechanistic insights.…”

Section: Introductionmentioning

confidence: 99%

Evidence for a Nuclear Role forDrosophilaDlg as a Regulator of the NURF Complex

Sharp

Khoury

Wirtz-Peitz

et al. 2021

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Scrib, Dlg, and Lgl are basolateral regulators of epithelial polarity and tumor suppressors whose molecular mechanisms of action remain unclear. We used proximity biotinylation to identify proteins localized near Dlg in the Drosophila wing imaginal disc epithelium. In addition to expected membrane- and cytoskeleton-associated protein classes, nuclear proteins were prevalent in the resulting mass spectrometry data set, including all four members of the NURF chromatin remodeling complex. Subcellular fractionation demonstrated a nuclear pool of Dlg and proximity ligation confirmed its position near the NURF complex. Genetic analysis showed that NURF activity is also required for the overgrowth of dlg tumors, and this growth suppression correlated with a reduction in Hippo pathway gene expression. Together, these data suggest a nuclear role for Dlg in regulating chromatin and transcription through a more direct mechanism than previously thought.

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“…The growth and origin of HSCs have been investigated using a variety of model systems. Haematopoiesis in vertebrates occurs in two distinctive organs and temporal frames: the primitive wave and the definitive wave or haematopoiesis 6 . In mammals, haematopoiesis occurs sequentially in the yolk sac, the fetal liver and the bone marrow (BM).…”

Section: Introductionmentioning

confidence: 99%

“…6 5-FU-treated (in the CML model) or 5 × 10 6 BM cells (in the B-ALL model) transduced with BCR-ABL1 were intravenously injected into sublethally irradiated young and old recipient mice. 18 hours later, BM and spleen were harvested and analysed by flow cytometry for BCR-ABL1 (GFP+) Lin-c-Kit+ (CML) or BCR-ABL1 (GFP+) BP-1+ (B-ALL) cells.…”

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The age of the bone marrow microenvironment influences B-cell acute lymphoblastic leukaemia progression via CXCR5-CXCL13

Zanetti¹

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B-cell acute lymphoblastic leukaemia (B-ALL) is characterized by the overproduction of lymphoblasts in the bone marrow (BM), and it is the most common cancer in children while being comparatively uncommon in adults. On the other hand, in chronic myeloid leukaemia (CML), 70% of cases are found in patients older than 50 years, making it uncommon in children. All CML cases and up to 3% of paediatric B- ALL (and 25% of adult B-ALL) cases are due to fusion gene BCR-ABL1, which gives rise to the cytoplasmatic, constitutively active oncoprotein, tyrosine kinase BCR-ABL1 through a reciprocal translocation between chromosomes 9 and 22. The constitutively active BCR-ABL tyrosine kinase leads to deregulation of different signal transduction pathways such as cell growth, proliferation and cell survival. The role of the bone marrow microenvironment (BMM) can mediate disease initiation (only in mice), progression, therapy resistance, and relapse, as has been increasingly recognized over the last two decades. In general, the BMM is a very complex arrangement of various cell types such as osteoblasts, osteoclasts, endothelial cells, adipocytes, mesenchymal stromal cells, macrophages and several others. In addition, the BMM is composed of multiple chemical and mechanical factors and extra cellular matrix (ECM) proteins which contribute to the BMM’s features influencing leukaemia behaviour. Considering the incidence of B-ALL and CML in children and in adults respectively, we hypothesized that the young and/or an aged BMM might also play a previously unrecognized role in the aggressiveness of B-ALL and CML. We proposed that BM, transduced with BCR-ABL1-expressing retrovirus in the murine transduction/transplantation model of B-ALL, transplanted into young versus old recipient mice would lead to a more aggressive disease in young mice, and similarly CML would be more aggressive in old recipient mice. In close recapitulation with the human incidence, induction of CML led to a significantly shorted survival in old recipient mice. On the other hand, induction of B-ALL showed a shortened survival in young compared to old syngeneic mice, as well as in a xenotransplantation model. Among the highly heterogenous composition of the BMM, we implicate young BM macrophages as a supportive niche for B-ALL cells. The results were found to be mostly due to potential soluble factors differentially secreted from young and old macrophages. Therefore, we hypothesized that the chemokine CXCL13, which has been demonstrated to play a role in B cell migration and act as a diagnostic marker in the cerebrospinal fluid of patients with neuroborreliosis, might be responsible for the observed phenotype. CXCL13 was found to be more highly expressed in healthy and leukaemic young mice as well as in conditioned medium of young macrophages. Using a variety of in vitro experiments, CXCL13 showed to significantly increase the proliferation and the migration of leukaemia cells when exposed to young macrophages, and the phenotype was rescued while using a CXCL13 neutralizing antibody. The CXCL13 role was also confirmed in vivo, since macrophage ablation led to a prolongation of survival in young mice and a reduction of CXCL13 levels. The use of an additional mouse model, leukaemia cells with CXCR5 deficiency, led to a significant prolongation of survival of young mice, confirming the importance of the CXCL13-CXCR5 axis in B-ALL. In line with our murine results, we found that human macrophages and CXCL13 levels were higher in pediatric B-ALL patients than in adults. Consistent with our murine data, the expression level of CXCR5 may act as a prognostic marker in B-ALL, as well as a predictive marker for central nervous system relapse in human B-ALL. The overall findings show that a young BMM, and in particular macrophages, influences B-ALL progression. We specifically identified CXCL13, secreted by young macrophages, as a promoter of proliferation of B-ALL cells, influencing survival in B-ALL via CXCR5. The CXCR5-CXCL13 axis may be relevant in human B-ALL, and higher CXCR5 expression in human B-ALL may act as a predictive marker.

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Diverging impact of cell fate determinants Scrib and Llgl1 on adhesion and migration of hematopoietic stem cells

Abstract: Our data provide first evidence for an evolutionarily conserved role of the cell fate determinant Scrib in HSC adhesion and migration in vitro and in vivo, a unique function that is not shared with its putative complex partner Llgl1.

Cited by 5 publications

References 33 publications

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Evidence for a Nuclear Role forDrosophilaDlg as a Regulator of the NURF Complex

The age of the bone marrow microenvironment influences B-cell acute lymphoblastic leukaemia progression via CXCR5-CXCL13

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