Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia

Zhang, Wan; Trachootham, Dunyaporn; Liu, Jinyun; Chen, Gang; Pélicano, Hélène; Garcı́a-Prieto, Celia; Lu, Weiqin; Burger, Jan A.; Croce, Carlo M.; Plunkett, William; Keating, Michael J.; Huang, Peng

doi:10.1038/ncb2432

Cited by 310 publications

(335 citation statements)

References 61 publications

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“…Although depletion of asparagine in serum and bone marrow aspirates can be monitored and shows complete depletion when asparaginase concentrations reach threshold levels, concentrations in situ and the supportive role of the microenvironment are the subject of debate (2,3,5,(15)(16)(17)(18). The question remains whether asparaginase is sufficiently active at this particular niche in which the leukemia originates and leukemia-initiating cells reside.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Imaging of Antileukemic Drug Asparaginase Reveals a Rapid Macrophage-Mediated Clearance from the Bone Marrow

et al. 2016

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The antileukemic drug asparaginase, a key component in the treatment of acute lymphoblastic leukemia, acts by depleting asparagine from the blood. However, little is known about its pharmacokinetics, and mechanisms of therapy resistance are poorly understood. Here, we explored the in vivo biodistribution of radiolabeled asparaginase, using a combination of imaging and biochemical techniques, and provide evidence for tissue-specific clearance mechanisms, which could reduce the effectiveness of the drug at these specific sites. Methods: In vivo localization of 111 In-labeled Escherichia coli asparaginase was performed in C57BL/6 mice by both small-animal SPECT/CT and ex vivo biodistribution studies. Mice were treated with liposomal clodronate to investigate the effect of macrophage depletion on tracer localization and drug clearance in vivo. Moreover, macrophage cell line models RAW264.7 and THP-1, as well as knockout mice, were used to identify the cellular and molecular components controlling asparaginase pharmacokinetics. Results: In vivo imaging and biodistribution studies showed a rapid accumulation of asparaginase in macrophage-rich tissues such as the liver, spleen, and in particular bone marrow. Clodronate-mediated depletion of phagocytic cells markedly prolonged the serum half-life of asparaginase in vivo and decreased drug uptake in these macrophage-rich organs. Immunohistochemistry and in vitro binding assays confirmed the involvement of macrophagelike cells in the uptake of asparaginase. We identified the activity of the lysosomal protease cathepsin B in macrophages as a rate-limiting factor in degrading asparaginase both in vitro and in vivo. Conclusion: We showed that asparaginase is rapidly cleared from the serum by liver-, spleen-, and bone marrow-resident phagocytic cells. As a consequence of this efficient uptake and protease-mediated degradation, particularly bone marrow-resident macrophages may provide a protective niche to leukemic cells.

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Section: Discussionmentioning

confidence: 99%

In Vivo Imaging of Antileukemic Drug Asparaginase Reveals a Rapid Macrophage-Mediated Clearance from the Bone Marrow

et al. 2016

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“…36,[40][41][42] In order to analyse the potential effect of these signals on SSA-induced apoptosis, we tried to mimic lymph node conditions in vitro. T cells are abundant in CLL lymph nodes, 43 Figure 6B).…”

Section: Ssa-induced Apoptosis Is Reduced In the Presence Of Microenvmentioning

confidence: 99%

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

et al. 2015

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The pro-survival Bcl-2 family member Mcl-1 is expressed in chronic lymphocytic leukemia (CLL), with high expression correlated with progressive disease. The spliceosome inhibitor spliceostatin A (SSA), is known to regulate Mcl-1 and so here we assessed the ability of SSA to elicit apoptosis in CLL. SSA induced apoptosis of CLL cells at low nanomolar concentrations in a dose-and time-dependent manner, but independently of SF3B1 mutational status, IGHV status and CD38 or ZAP70 expression.However, normal B and T cells were less sensitive than CLL cells (p=0.006 and p<0.001, respectively).

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“…GSH availability depends primarily on its synthesis obtained by condensation of cysteine, glutamate and glycine. Cysteine transport is under the control of the glutamate-cystine xCT transporter, 101,102 whereas the availability of glutamate depends on activity of glutaminase, target of p53 and Myc factors. Glycine is not only a component of GSH, but also represents a major source for biosynthesis of purines and heme group, 103 and of methyl groups for the socalled one-carbon metabolism, a complex network that based on folate compounds, well-known targets of antifolate chemotherapy.…”

Section: Oxidative Stress Pathwaysmentioning

confidence: 99%

Uncovering metabolism in rhabdomyosarcoma

Monti

Fanzani

2016

Cell Cycle

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Rhabdomyosarcoma (RMS) is a myogenic tumor classified as the most frequent soft tissue sarcoma affecting children and adolescents. The histopathological classification includes five different histotypes, with two most predominant referred as to embryonal and alveolar, the latter being characterized by adverse outcome. The current molecular classification identifies two major subsets, those harboring the fused Pax3-Foxo1 transcription factor generating from a recurrent specific translocation (fusion-positive RMS), and those lacking this signature but harboring mutations in the RAS/PI3K/AKT signalling axis (fusion-negative RMS). Since little attention has been devoted to RMS metabolism until now, in this review we summarize the “state of art” of metabolism and discuss how some of the molecular signatures found in this cancer, as observed in other more common tumors, can predict important metabolic challenges underlying continuous cell growth, oxidative stress resistance and metastasis, which could be the subject of future targeted therapies

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Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia

Cited by 310 publications

References 61 publications

In Vivo Imaging of Antileukemic Drug Asparaginase Reveals a Rapid Macrophage-Mediated Clearance from the Bone Marrow

In Vivo Imaging of Antileukemic Drug Asparaginase Reveals a Rapid Macrophage-Mediated Clearance from the Bone Marrow

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

Uncovering metabolism in rhabdomyosarcoma

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