Acute Myeloid Leukaemia in Its Niche: the Bone Marrow Microenvironment in Acute Myeloid Leukaemia

Ladikou, Eleni E; Sivaloganathan, Helena; Buggins, Andrea Pepper née; Chevassut, Timothy

doi:10.1007/s11912-020-0885-0

Cited by 52 publications

(52 citation statements)

References 83 publications

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“…Thus, low ROS contents have been associated with stemness and quiescence [ 13 , 17 , 20 , 23 ] while intermediate ROS levels were found in more differentiated populations and associated to proliferation and differentiation [ 49 ]. The importance of the microenvironment has also been emphasized, not only in the maintenance of normal hematopoiesis homeostasis [ 10 , 50 , 51 ] but also in leukemic development [ 52 ]. In this study, we used a coculture system composed of primary MSCs from healthy donors and AML cells (cell-lines or primary blasts) to model the leukemic niche and dissect molecular pathways reciprocally induced in the field of redox metabolism.…”

Section: Discussionmentioning

confidence: 99%

Involvement of GPx-3 in the Reciprocal Control of Redox Metabolism in the Leukemic Niche

Vignon

Debeissat

Bourgeais

et al. 2020

IJMS

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The bone marrow (BM) microenvironment plays a crucial role in the development and progression of leukemia (AML). Intracellular reactive oxygen species (ROS) are involved in the regulation of the biology of leukemia-initiating cells, where the antioxidant enzyme GPx-3 could be involved as a determinant of cellular self-renewal. Little is known however about the role of the microenvironment in the control of the oxidative metabolism of AML cells. In the present study, a coculture model of BM mesenchymal stromal cells (MSCs) and AML cells (KG1a cell-line and primary BM blasts) was used to explore this metabolic pathway. MSC-contact, rather than culture with MSC-conditioned medium, decreases ROS levels and inhibits the Nrf-2 pathway through overexpression of GPx3 in AML cells. The decrease of ROS levels also inactivates p38MAPK and reduces the proliferation of AML cells. Conversely, contact with AML cells modifies MSCs in that they display an increased oxidative stress and Nrf-2 activation, together with a concomitant lowered expression of GPx-3. Altogether, these experiments suggest that a reciprocal control of oxidative metabolism is initiated by direct cell–cell contact between MSCs and AML cells. GPx-3 expression appears to play a crucial role in this cross-talk and could be involved in the regulation of leukemogenesis.

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Section: Discussionmentioning

confidence: 99%

Involvement of GPx-3 in the Reciprocal Control of Redox Metabolism in the Leukemic Niche

Vignon

Debeissat

Bourgeais

et al. 2020

IJMS

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“…Indeed, most AML blasts and especially LSCs acquire CXCR4 expression [44,45]. Moreover, high CXCR4 expression on AML is a negative prognostic factor associated with reduced overall and relapse-free survival [46]. CXCL12, similarly to its multi-functional effects on HSCs, acts as a pleiotropic chemokine also in AML.…”

Section: Cxcl12-cxcr4 Axismentioning

confidence: 99%

“…Mohle et al first reported a role of CXCL12-CXCR4 axis in the regulation of AML cells homing and engraftment in the BM niche [47]. Moreover, CXCL12-CXCR4 contributes to AML chemoresistance, as it keeps leukemic cells in close contact with extracellular matrix components, like the integrin VLA-4 and the hyaluronate receptor CD44 [46], and with stromal cells that constitutively secrete growth-promoting and anti-apoptotic signals [48,49].…”

Section: Cxcl12-cxcr4 Axismentioning

confidence: 99%

“…Considering the pathogenic role of CXCL12-CXCR4 axis in AML, much effort has been put toward finding strategies inducing its blockade [42,46]. Overall, four main classes of CXCR4 antagonists and agonists have been developed: (1) small peptide CXCR4 antagonists, like TN140 and its analogs [50], (2) non-peptide CXCR4 antagonists, such as Plerixafor (AMD3100), (3) mAbs against CXCR4, such as the fully human antibody Ulocuplumab [51,52], and finally, (4) modified agonist and antagonists for CXCL12 [53].…”

Section: Cxcl12-cxcr4 Axismentioning

confidence: 99%

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Location First: Targeting Acute Myeloid Leukemia Within Its Niche

Pievani

Biondi

Tomasoni

et al. 2020

JCM

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Despite extensive research and development of new treatments, acute myeloid leukemia (AML)-backbone therapy has remained essentially unchanged over the last decades and is frequently associated with poor outcomes. Eradicating the leukemic stem cells (LSCs) is the ultimate challenge in the treatment of AML. Emerging evidence suggests that AML remodels the bone marrow (BM) niche into a leukemia-permissive microenvironment while suppressing normal hematopoiesis. The mechanism of stromal-mediated protection of leukemic cells in the BM is complex and involves many adhesion molecules, chemokines, and cytokines. Targeting these factors may represent a valuable approach to complement existing therapies and overcome microenvironment-mediated drug resistance. Some strategies for dislodging LSCs and leukemic blasts from their protective niche have already been tested in patients and are in different phases of the process of clinical development. Other strategies, such as targeting the stromal cells remodeling processes, remain at pre-clinical stages. Development of humanized xenograft mouse models, which overcome the mismatch between human leukemia cells and the mouse BM niche, is required to generate physiologically relevant, patient-specific human niches in mice that can be used to unravel the role of human AML microenvironment and to carry out preclinical studies for the development of new targeted therapies.

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“…Leukemogenesis is characterized by uncontrolled clonal proliferation of malignant leukemic cells (blasts) that have lost the ability of proper differentiation at various stages of maturation. Our knowledge today suggests that leukemic blasts transduce the surrounding BMM into a leukemia-supportive niche and vice-versa, pointing at a bidirectional crosstalk between leukemic blasts and BMM reciprocally supporting further disease progression [ 1 ]. In adults, AML represents the most common form of acute leukemia whilst in pediatrics, it accounts for 20% of all childhood leukemias with an overall survival of about 70% that ranges from 60% to 90% depending on the risk profile [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Redirecting the Immune Microenvironment in Acute Myeloid Leukemia

Sendker¹,

Reinhardt²,

Niktoreh³

2021

Cancers

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Acute myeloid leukemia is a life-threatening malignant disorder arising in a complex and dysregulated microenvironment that, in part, promotes the leukemogenesis. Treatment of relapsed and refractory AML, despite the current overall success rates in management of pediatric AML, remains a challenge with limited options considering the heavy but unsuccessful pretreatments in these patients. For relapsed/refractory (R/R) patients, hematopoietic stem cell transplantation (HSCT) following ablative chemotherapy presents the only opportunity to cure AML. Even though in some cases immune-mediated graft-versus-leukemia (GvL) effect has been proven to efficiently eradicate leukemic blasts, the immune- and chemotherapy-related toxicities and adverse effects considerably restrict the feasibility and therapeutic power. Thus, immunotherapy presents a potent tool against acute leukemia but needs to be engineered to function more specifically and with decreased toxicity. To identify innovative immunotherapeutic approaches, sound knowledge concerning immune-evasive strategies of AML blasts and the clinical impact of an immune-privileged microenvironment is indispensable. Based on our knowledge to date, several promising immunotherapies are under clinical evaluation and further innovative approaches are on their way. In this review, we first focus on immunological dysregulations contributing to leukemogenesis and progression in AML. Second, we highlight the most promising therapeutic targets for redirecting the leukemic immunosuppressive microenvironment into a highly immunogenic environment again capable of anti-leukemic immune surveillance.

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Acute Myeloid Leukaemia in Its Niche: the Bone Marrow Microenvironment in Acute Myeloid Leukaemia

Cited by 52 publications

References 83 publications

Involvement of GPx-3 in the Reciprocal Control of Redox Metabolism in the Leukemic Niche

Involvement of GPx-3 in the Reciprocal Control of Redox Metabolism in the Leukemic Niche

Location First: Targeting Acute Myeloid Leukemia Within Its Niche

Redirecting the Immune Microenvironment in Acute Myeloid Leukemia

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