CXCR4 Signaling Has a CXCL12-Independent Essential Role in Murine MLL-AF9-Driven Acute Myeloid Leukemia

Ramakrishnan, Ramprasad; Peña-Martínez, Pablo; Agarwal, Puneet; Rodriguez‐Zabala, Maria; Chapellier, Marion; Högberg, Carl; Eriksson, Mia; Yudovich, David; Shah, Mansi; Ehinger, Mats; Nilsson, Björn; Larsson, Jonas; Hagström-Andersson, Anna; Ebert, Benjamin L.; Bhatia, Ravi; Järås, Marcus

doi:10.1016/j.celrep.2020.107684

Cited by 33 publications

(31 citation statements)

References 79 publications

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“…37 Recently, a murine MLL-AF9-driven AML model was used to evaluate the engraftment of leukaemia cells into mouse BM. 38 The deletion of cxcr4 in AML cells eradicated leukaemia cells in vivo, but their homing to the BM was not impaired. Furthermore, SDF-1 is dispensable for the development of leukaemia in mice.…”

Section: Cxcr4 Participates In Homing and Residence Of Aml Cells In Bmmentioning

confidence: 99%

Role of CXCR4 in the progression and therapy of acute leukaemia

Yang

2021

Cell Proliferation

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Chemokines are small peptides with molecular weights of 8-12 KDa, which are secreted by multiple types of cells, such as immune cells, stromal cells and tumour cells. Chemokine receptors are seven-transmembrane G-protein-coupled receptors (GPCRs), and one receptor can bind to multiple chemokines. 1,2 Conversely, one chemokine can recognize several receptors. 1,2 CXCR4 was first discovered as a cofactor facilitating the entry of human immunodeficiency virus (HIV) into CD4 + T cells and was then classified into GPCR subfamily. 3,4 CXCR4 is widely expressed in many types of cells, including haematopoietic stem cells (HSCs), T lymphocytes, B lymphocytes, monocytes, macrophages, epithelial cells, endothelial cells and neurons. 5 Stromal-derived factor 1 (SDF-1), also known as CXCL12, is the only ligand for CXCR4 but can also bind to CXCR7.After the engagement of SDF-1 and CXCR4, many intracellular pathways are activated, including RAS-MAPK, PI3K-AKT-mTOR and JAK-STAT, which then regulate chemotaxis, gene expression and cell survival. 6,7 Sdf1 or Cxcr4 homozygous mutations in mice resulted in embryonic lethality, and the development of B lymphocytes and myeloid cells was severely impaired. 8,9 Other defects, including cardiac ventricular septal defect and defective formation of large vessels supplying the gastrointestinal tracts, were found. 10 HSCs express high levels of CXCR4 and can migrate from the foetal

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Section: Cxcr4 Participates In Homing and Residence Of Aml Cells In Bmmentioning

confidence: 99%

Role of CXCR4 in the progression and therapy of acute leukaemia

Yang

2021

Cell Proliferation

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“…Recently, Ramakrishnan et al ( 150 ) demonstrated that CXCR4 alone provides sufficient signaling in the absence of CXCL12 ligation to promote the expansion and survival of murine AML cells in vivo . Therefore, if CXCR4 expression is maintained, disruption of the CXCR4/CXL12 axis alone might be insufficient to effectively sensitize leukemic cells to cytotoxic chemotherapy.…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

Targeting CXCR4 in AML and ALL

2020

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The interaction of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) blasts with the bone marrow microenvironment regulates self-renewal, growth signaling, as well as chemotherapy resistance. The chemokine receptor, CXC receptor 4 (CXCR4), with its ligand chemokine ligand 12 (CXCL12), plays a key role in the survival and migration of normal and malignant stem cells to the bone marrow. High expression of CXCR4 on AML and ALL blasts has been shown to be a predictor of poor prognosis for these diseases. Several small molecule inhibitors, short peptides, antibodies, and antibody drug conjugates have been developed for the purposes of more effective targeting and killing of malignant cells expressing CXCR4. In this review we will discuss recent results and strategies in targeting CXCR4 with these agents in patients with AML or ALL.

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“…Interestingly, CXCL12 was dispensable for leukemia development, whereas CXCR4 signaling was essential for AML cells preventing their differentiation. Importantly, these data demonstrate that beyond its role in mediating crosstalk to the microenvironment, CXCR4 acts also cell-intrinsically, triggering key signaling cascades promoting and maintaining the malignant phenotype of the cell 28 . As expected, EPI-X4 impaired phosphorylation of the MAPK pathway, documented by FACS and PAMChip-based quantification of phosphorylation of members of this pathway and validated by Western blot.…”

Section: Discussionmentioning

confidence: 90%

Acute myeloid leukemia cells are targeted by the naturally occurring CXCR4 antagonist EPI-X4

Kaiser

Harms

Sauter

et al. 2021

Preprint

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The G protein-coupled receptor (GPCR) and chemokine receptor CXCR4 plays an essential role in tumor initiation and maintenance. This is exemplified in acute myeloid leukemia (AML), where CXCL12-mediated CXCR4 signaling plays a pivotal role for the crosstalk between leukemic stem cells and their microenvironmental niche. Despite the key role of CXCR4 in cancer, surprisingly little is known about endogenous mechanisms that specifically target CXCR4 and dampen its activity. Here, we demonstrate that the naturally occurring peptide and CXCR4 antagonist EPI-X4 and its optimized derivatives effectively blocks CXCL12-mediated migration of AML cells towards a CXCL12 gradient and impairs growth of AML cells in vitro and in vivo in contrast to normal hematopoietic stem and progenitor cells. This anti-leukemic activity of EPI-X4 was accompanied by suppression of CXCR4-mediated MAPK signaling. Of note, EPI-X4 suppressed metabolic pathways and induced depletion of intracellular nicotinamide phosphoribosyltransferase (iNAMPT) in AML cells, linking anti-CXCR4 activity to shifts in NAD+ metabolism.

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CXCR4 Signaling Has a CXCL12-Independent Essential Role in Murine MLL-AF9-Driven Acute Myeloid Leukemia

Abstract: Highlights d In vivo CRISPR screening identifies CXCR4 as a key regulator of AML stem cells d CXCL12 expression in the bone marrow is dispensable for AML development d CXCR4 signaling protects AML cells from oxidative stress and differentiation

Cited by 33 publications

References 79 publications

Role of CXCR4 in the progression and therapy of acute leukaemia

Role of CXCR4 in the progression and therapy of acute leukaemia

Targeting CXCR4 in AML and ALL

Acute myeloid leukemia cells are targeted by the naturally occurring CXCR4 antagonist EPI-X4

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