B-cell precursor acute lymphoblastic leukemia cells use tunneling nanotubes to orchestrate their microenvironment

Abstract

Key Points• Primary BCP-ALL cells use tunneling nanotubes to signal to mesenchymal stromal cells and thereby trigger cytokine secretion.• Inhibiting tunneling nanotube signaling is a promising approach to induce apoptosis and sensitize BCP-ALL cells toward prednisolone.Acute lymphoblastic leukemia (ALL) cells reside in the bone marrow microenvironment which nurtures and protects cells from chemotherapeutic drugs. IntroductionAcute lymphoblastic leukemia (ALL) cells reside in the local microenvironment of the bone marrow and are able to disrupt normal hematopoietic stem cell niches.1 The disrupted, so-called leukemic, niche is essential in initiating and facilitating leukemogenesis. [2][3][4][5][6] In addition, the leukemic niche protects leukemic cells from elimination by immune responses and chemotherapeutic agents, and can facilitate the development of drug resistance of leukemic cells.7-10 Therefore, the disruption of the ALL-leukemic niche interaction offers a promising new therapeutic strategy.11-16 However, it is still largely unclear how crosstalk occurs within the leukemic niche, and how this drives leukemic cell survival and chemotherapy resistance.Recently, tunneling nanotubes (TNTs), or membrane nanotubes, have been described as a novel mode of communication between eukaryotic cells. [17][18][19][20][21] TNTs are thin membrane protrusions consisting of F-actin, that connect cells and facilitate the transport of several types of cargo, including organelles, pathogens, calcium fluxes, death signals, and membrane-bound proteins. 19,20,[22][23][24] These intercellular membrane conduits have been observed in several cell types, like cancer cells, complex tissues, and organisms. 20,21,[24][25][26][27][28][29] The pathophysiological importance of TNTs has become evident by studies showing that prions and HIV-1 particles use TNTs to promote disease spread. 21,30 However, the presence of TNTs within the leukemic niche and hence their role in communication between leukemic cells and the bone marrow microenvironment has not yet been addressed. Here, we study the role of TNT signaling in communication between primary B-cell precursor ALL (BCP-ALL) cells and mesenchymal stromal cells (MSCs), and the contribution of TNT signaling to mesenchymal-mediated survival and resistance to the chemotherapeutic drug prednisolone. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. For personal use only. on May 12, 2018. by guest www.bloodjournal.org From Primary patient-derived materialBone marrow aspirates were obtained from children with newly diagnosed BCP-ALL prior to treatment. Mononuclear leukemic cells were collected and processed as previously described. 31 All samples used in this study contained $97% leukemic blasts (supplemental Figure 7, see supplemental Data available at the Blood Web site). MSCs were isolated from bone marrow aspirates obtained from n...

Pro-inflammatory-Related Loss of CXCL12 Niche Promotes Acute Lymphoblastic Leukemic Progression at the Expense of Normal Lymphopoiesis

“…Remarkably, the cellular communication between leukemic cells and MSC through exosomes or across nanotubes (65, 66) and the disruption of the CXCR4/CXCL12 axis (28, 59), suggesting a key role for G-CSF in this phenomena, are consistent with our previous reports about production of pro-inflammatory factors by tumor cells (30), related to G-CSF and Gfi-1 (29). Accordingly, G-CSF administration in a preclinical model of ALL showed an increased tumor burden (67), and its mechanism may be operating in the niche because B cell malignances rarely expressed G-CSF receptor and are unable to respond in vitro to this cytokine (68).…”

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

“…4 Homing of ALL cells toward the bone marrow microenvironment is thought to be similar to that of hematopoietic stem cells (HSCs). 5 Human CD34 + progenitor cells, are attracted by stromal cell-derived factor 1 (SDF-1/CXCL12), a chemoattractant actively produced by MSCs in the bone marrow.…”

Tunneling nanotube (TNT) formation is downregulated by cytarabine and NF-κB inhibition in acute myeloid leukemia (AML)

“…These intercellular structures are also exploited for cell-to-cell transfer by pathogens [17–23] and evidence for TNT-like structures and TNTs in vivo has been provided in zebrafish embryos, in neural crest cells in chick embryos, in adult mouse cornea, as well as lung cancer biopsies [10, 24–28]. Recently, it was demonstrated that B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells and mesenchymal stem cells (MSCs) formed TNTs involving pro-survival cytokines and leukemic niche therapy resistance [29]. …”