Distinct roles of mesenchymal stem and progenitor cells during the development of acute myeloid leukemia in mice

Xiao, Pengnan; Sandhow, Lakshmi; Heshmati, Yaser; Kondō, Makoto; Bouderlique, Thibault; Dolinska, Monika B.; Johansson, Anne; Sigvardsson, Mikael; Ekblom, Marja; Walfridsson, Julian; Qian, Hong

doi:10.1182/bloodadvances.2017013870

Cited by 29 publications

(55 citation statements)

References 47 publications

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“…Murine models of AML revealed a dramatically impaired HSC-regulating capacity of bone marrow MSPCs. 5,30,31 In fact, we also observed significantly lower expression of HSC-regulating genes in MSPCs from AML patients that correlates with an impaired capacity to maintain HSPCs in vitro, as our group has recently shown. 20 The decreased expression of HSCregulating factors were referred to a more differentiated state of MSPCs in murine AML.…”

Section: Discussionsupporting

confidence: 79%

“…20 The decreased expression of HSCregulating factors were referred to a more differentiated state of MSPCs in murine AML. 5,31 Our microarray data revealed decreased expression of osteogenesis-related gene sets in MSPCs isolated from AML patients correlating with AML-specific inhibition of osteoblast maturation in a cell contact-dependent manner in our coculture model. Loss of mature osteoblasts in AML has been observed in murine AML models.…”

Section: Discussionmentioning

confidence: 85%

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Acute myeloid leukemia–induced remodeling of the human bone marrow niche predicts clinical outcome

et al. 2020

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Murine models of myeloid neoplasia show how leukemia infiltration alters the hematopoietic stem cell (HSC) niche to reinforce malignancy at the expense of healthy hematopoiesis. However, little is known about the bone marrow architecture in humans and its impact on clinical outcome. Here, we dissect the bone marrow niche in patients with acute myeloid leukemia (AML) at first diagnosis. We combined immunohistochemical stainings with global gene expression analyses from these AML patients and correlated them with clinical features. Mesenchymal stem and progenitor cells (MSPCs) lost quiescence and significantly expanded in the bone marrow of AML patients. Strikingly, their HSC- and niche-regulating capacities were impaired with significant inhibition of osteogenesis and bone formation in a cell contact–dependent manner through inhibition of cytoplasmic β-catenin. Assessment of bone metabolism by quantifying peripheral blood osteocalcin levels revealed 30% lower expression in AML patients at first diagnosis than in non-leukemic donors. Furthermore, patients with osteocalcin levels ≤11 ng/mL showed inferior overall survival with a 1-year survival rate of 38.7% whereas patients with higher osteocalcin levels reached a survival rate of 66.8%. These novel insights into the human AML bone marrow microenvironment help translate findings from preclinical models and detect new targets which might pave the way for niche-targeted therapies in AML patients.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 85%

Acute myeloid leukemia–induced remodeling of the human bone marrow niche predicts clinical outcome

et al. 2020

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“…CD44 would be assumed to be working via the CD74/CD44 axis [[19], [20], [21]]. SPP1 has recently been shown to be an important component in maintaining the tumor microenvironment in AML [61]. SPP1 is known to interact with various integrins and LGALS3 is a regulator of integrin function so perhaps integrin-mediated signaling is involved [1,2,62].…”

Section: Discussionmentioning

confidence: 99%

LGALS3 is connected to CD74 in a previously unknown protein network that is associated with poor survival in patients with AML

Ruvolo

Qiu

et al. 2019

eBioMedicine

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Background Galectin 3 (LGALS3) gene expression is associated with poor survival in acute myeloid leukemia (AML) but the prognostic impact of LGALS3 protein expression in AML is unknown. LGALS3 supports diverse survival pathways including RAS mediated cascades, protein expression and stability of anti-apoptotic BCL2 family members, and activation of proliferative pathways including those mediated by beta Catenin. CD74 is a positive regulator of CD44 and CXCR4 signaling and this molecule may be critical for AML stem cell function. At present, the role of LGALS3 and CD74 in AML is unclear. In this study, we examine protein expression of LGALS3 and CD74 by reverse phase protein analysis (RPPA) and identify new protein networks associated with these molecules. In addition, we determine prognostic potential of LGALS3, CD74, and their protein networks for clinical correlates in AML patients. Methods RPPA was used to determine relative expression of LGALS3, CD74, and 229 other proteins in 231 fresh AML patient samples and 205 samples were from patients who were treated and evaluable for outcome. Pearson correlation analysis was performed to identify proteins associated with LGALS3 and CD74. Progeny clustering was performed to generate protein networks. String analysis was performed to determine protein:protein interactions in networks and to perform gene ontology analysis. Kaplan-Meir method was used to generate survival curves. Findings LGALS3 is highest in monocytic AML patients and those with elevated LGALS3 had significantly shorter remission duration compared to patients with lower LGALS3 levels (median 21.9 vs 51.3 weeks, p = 0.016). Pearson correlation of LGALS3 with 230 other proteins identifies a distinct set of 37 proteins positively correlated with LGALS3 expression levels with a high representation of proteins involved in AKT and ERK signaling pathways. Thirty-one proteins were negatively correlated with LGALS3 including an AKT phosphatase. Pearson correlation of proteins associated with CD74 identified 12 proteins negatively correlated with CD74 and 16 proteins that are positively correlated with CD74. CD74 network revealed strong association with CD44 signaling and a high representation of apoptosis regulators. Progeny clustering was used to build protein networks based on LGALS3 and CD74 associated proteins. A strong relationship of the LGALS3 network with the CD74 network was identified. For AML patients with both the LGALS3 and CD74 protein cluster active, median overall survival was only 24.3 weeks, median remission duration was 17.8 weeks, and no patient survived beyond one year. Interpretation The findings from this study identify for the first time protein networks associated with LGALS3 and CD74 in AML. Each network features unique pathway characteristics. The data also suggest that the LGALS3 network and the CD74 network each support AML cell survival and the two netwo...

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“…It was shown in mouse AML models that AML cells extensively reorganize the cellular, physical, and transcriptional niche architecture to facilitate their own expansion (25)(26)(27) and provide protection from cytotoxic chemotherapy (28). The leukemic BM contains a dysregulated vascular and mesenchymal network with reduced perfusion and oxygen availability (28,29).…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal niche remodeling impairs hematopoiesis via stanniocalcin 1 in acute myeloid leukemia

Waclawiczek¹,

Hamilton²,

Rouault-Pierre³

et al. 2020

Journal of Clinical Investigation

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Distinct roles of mesenchymal stem and progenitor cells during the development of acute myeloid leukemia in mice

Cited by 29 publications

References 47 publications

Acute myeloid leukemia–induced remodeling of the human bone marrow niche predicts clinical outcome

Acute myeloid leukemia–induced remodeling of the human bone marrow niche predicts clinical outcome

LGALS3 is connected to CD74 in a previously unknown protein network that is associated with poor survival in patients with AML

Mesenchymal niche remodeling impairs hematopoiesis via stanniocalcin 1 in acute myeloid leukemia

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