Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase

Iwamoto, Shotaro; Mihara, Keichiro; Downing, James R.; Pui, Ching‐Hon; Campana, Dario

doi:10.1172/jci30235

Cited by 306 publications

(260 citation statements)

References 44 publications

(44 reference statements)

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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%

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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%

“…It has been suggested that during asparaginase treatment, leukemic cell survival is supported by asparagine released by surrounding mesenchymal cells (2,3). Although asparagine levels are significantly higher in bone marrow aspirates than in matched blood samples, these levels drop after treatment with asparaginase (4,5).…”

mentioning

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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“…76 One of the mechanisms by which MSCs protect ALL cells from chemotherapeutic agents is related to asparagine synthetase, an enzyme that is critical to the biosynthesis of asparagine. MSCs constitutively secrete asparagine synthetase, 125 which interferes with asparaginase, a drug that has a critical impact in the treatment of ALL patients. Through this mechanism, ALL cells may survive in marrow stromal niches and thus represent the seed for residual disease and relapses.…”

Section: Acute Myeloid Leukemiamentioning

confidence: 99%

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

Burger

Peled²

2008

Leukemia

414

316

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“…The BM microenvironment plays a role in the pathogenesis of a variety of hematological malignancies including acute lymphoblastic leukemia (ALL), multiple myeloma or myelodysplastic syndrome [93][94][95]. The onset and progression of hematological malignancies are in many cases dependent on mutual interactions between the leukemic blasts/plasma cells and BM stroma/MSCs, which provide survival and growth-promoting signals [8,95,96].…”

Section: Mscs and Tumor Growthmentioning

confidence: 99%

“…The onset and progression of hematological malignancies are in many cases dependent on mutual interactions between the leukemic blasts/plasma cells and BM stroma/MSCs, which provide survival and growth-promoting signals [8,95,96]. Interestingly, the fusion MLL-AF4 was recently found expressed in both BM-MSCs and leukemic blasts in 100% of infants suffering from pro-B ALL highlighting an unrecognized role of the BM milieu in the pathogenesis of this dismal infant leukemia [97].…”

Section: Mscs and Tumor Growthmentioning

confidence: 99%

Modeling sarcomagenesis using multipotent mesenchymal stem cells

2011

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Because of their unique properties, multipotent mesenchymal stem cells (MSCs) represent one of the most promising adult stem cells being used worldwide in a wide array of clinical applications. Overall, compelling evidence supports the long-term safety of ex vivo expanded human MSCs, which do not seem to transform spontaneously. However, experimental data reveal a link between MSCs and cancer, and MSCs have been reported to inhibit or promote tumor growth depending on yet undefined conditions. Interestingly, solid evidence based on transgenic mice and genetic intervention of MSCs has placed these cells as the most likely cell of origin for certain sarcomas. This research area is being increasingly explored to develop accurate MSC-based models of sarcomagenesis, which will be undoubtedly valuable in providing a better understanding about the etiology and pathogenesis of mesenchymal cancer, eventually leading to the development of more specific therapies directed against the sarcoma-initiating cell. Unfortunately, still little is known about the mechanisms underlying MSC transformation and further studies are required to develop bona fide sarcoma models based on human MSCs. Here, we comprehensively review the existing MSC-based models of sarcoma and discuss the most common mechanisms leading to tumoral transformation of MSCs and sarcomagenesis.

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Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase

Cited by 306 publications

References 44 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

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

Modeling sarcomagenesis using multipotent mesenchymal stem cells

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