Long-term culture of infant leukemia cells: Dependence upon stromal cells from the bone marrow and bilineage differentiation

Umiel, Tehila; Friedman, Sari; Zaizov, Rina; Cohen, Ian J.; Gozes, Yehoshua; Epstein, Neal D.; Kobiler, David; Zipori, Dov

doi:10.1016/0145-2126(86)90253-5

Cited by 36 publications

(14 citation statements)

References 19 publications

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“…Leukemic lymphoblasts isolated from bone marrow rapidly die in standard culture media, but thrive on layers of bone marrow MSCs (25)(26)(27)(28)(29)(30), suggesting their dependence on survival factors produced within this microenvironment. We therefore studied ASNS expression levels in bone marrow-derived MSCs.…”

Section: Introductionmentioning

confidence: 99%

“…Direct contact with bone marrow MSCs is essential for the long-term survival and expansion of leukemic lymphoblasts in vitro (25)(26)(27)(28)(29), and their capacity to grow on MSCs is a predictor of treatment outcome in childhood ALL (30). We suspected that MSC niches might confer some degree of protection against asparaginase cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Iwamoto

Mihara²,

Downing³

et al. 2007

J. Clin. Invest.

305

255

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Iwamoto

Mihara²,

Downing³

et al. 2007

J. Clin. Invest.

305

255

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“…20 Phenotypic characteristics also are preserved in bone marrow stromal culture. 21 The response of leukemic blasts to chemotherapeutic agents in the NOD/SCID xenograft model has been shown to directly correlate to human response to therapy. 22 We studied the efficacy of a second generation MTI, CCI-779 (temsirolimus), in primary human ALL in both NOD/SCID xenografts and a bone marrow stromal culture system, demonstrating activity of this class of drugs against adult ALL.…”

Section: Introductionmentioning

confidence: 99%

The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL

Teachey

Obzut

Cooperman

et al. 2006

Blood

158

128

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Acute lymphoblastic leukemia (ALL) in adult patients is often resistant to current therapy, making the development of novel therapeutic agents paramount. We investigated whether mTOR inhibitors (MTIs), a class of signal transduction inhibitors, would be effective in primary human ALL. Lymphoblasts from adult patients with precursor B ALL were cultured on bone marrow stroma and were treated with CCI-779, a second generation MTI. Treated cells showed a dramatic decrease in cell proliferation and an increase in apoptotic cells, compared to untreated cells. We also assessed the effect of CCI-779 in a NOD/SCID xenograft model. We treated a total of 68 mice generated from the same patient samples with CCI-779 after establishment of disease. Animals treated with CCI-779 showed a decrease in peripheralblood blasts and in splenomegaly. In dramatic contrast, untreated animals continued to show expansion of human ALL. We performed immunoblots to validate the inhibition of the mTOR signaling intermediate phospho-S6 in human ALL, finding down-regulation of this target in xenografted human ALL exposed to CCI-779. We conclude that MTIs can inhibit the growth of adult human ALL and deserve close examination as therapeutic agents against a disease that is often not curable with current therapy. IntroductionWhile children with precursor B-cell acute lymphoblastic leukemia (ALL) are often cured, children with relapsed ALL and adults with ALL usually succumb to their disease with current therapy. Even with aggressive therapy, these patient groups have 5-year diseasefree survival rates of only 28% to 39%. 1 Thus, the development of novel therapeutic agents is crucial.One potential class of novel therapeutics is mTOR inhibitors (MTIs). MTIs are a class of signal transduction inhibitors with anticancer activity that were initially developed as immunosuppressive agents. [2][3][4][5] Rapamycin, a macrocyclic lactone produced by Streptomyces hydroscopicus, 6 was the first MTI to be used in a clinical setting. Rapamycin is well tolerated in humans. 7 MTIs also have been shown to be active against a wide variety of tumor types. [8][9][10] We have previously shown that rapamycin induces apoptosis in precursor B ALL lines in vitro and has in vivo activity in transgenic mice with pre-B leukemia/lymphoma. 11 Second generation MTIs, CCI-779 and RAD-001, are currently in phase 1 to phase 3 clinical trials in patients with various cancers, 12-15 but preclinical studies have not previously been performed in primary human ALL.Preclinical testing of chemotherapeutic agents often involves using transformed tumor lines and transgenic mouse models. While these are valuable tools, they may not be representative of human disease. More clinically relevant data may be obtained from systems using primary human ALL cells. Two of these systems, bone marrow stroma-supported culture 16 and xenografting human ALL in nonobese diabetic/severe combined immunodeficient (NOD/ SCID) mice, have recently been developed. 17 Both of these systems allow for direct testing...

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“…There is evidence that leukemic cells grow and accumulate in close association with bone marrow MSC which might regulate their differentiation. 3 In the case of acute lymphoblastic leukemia, MSC have been shown to regulate response to cytotoxic agents by directly interfering with their mechanisms of action. 4 Chronic myeloid leukemia (CML) is caused by the malignant transformation of a hematopoietic stem cell and is characterized by the Philadelphia chromosome (Ph1), a reciprocal translocation of chromosomes 9 and 22, which generates the BCR/ABL fusion gene encoding a constitutively active tyrosine kinase.…”

Section: Introductionmentioning

confidence: 99%

Bone marrow mesenchymal stromal cells non-selectively protect chronic myeloid leukemia cells from imatinib-induced apoptosis via the CXCR4/CXCL12 axis

Vianello¹,

Villanova²,

Tisato³

et al. 2010

Haematologica

152

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The online version of this article has a Supplementary Appendix. BackgroundResidual chronic myeloid leukemia disease following imatinib treatment has been attributed to the presence of quiescent leukemic stem cells intrinsically resistant to imatinib. Mesenchymal stromal cells in the bone marrow may favor the persistence and progression of leukemia by preserving the proliferation and self-renewal capacities of the malignant progenitor cells. Design and MethodsBV173 or primary chronic myeloid leukemia cells were co-cultured with human mesenchymal stromal cells and imatinib-induced cell death was then measured. The roles of pro-and antiapoptotic proteins and chemokine CXCL12 in this context were evaluated. We also studied the ability of BV173 cells to repopulate NOD/SCID mice following in vitro exposure to imatinib and mesenchymal stromal cells. ResultsWhilst imatinib induced dose-dependent apoptosis of BV173 cells and primary chronic myeloid leukemia cells, co-culture with mesenchymal stromal cells protected both types of chronic myeloid leukemia cells. Molecular analysis indicated that mesenchymal stromal cells reduced caspase-3 activation and modulated the expression of the anti-apoptotic protein Bcl-XL. Furthermore, chronic myeloid leukemia cells exposed to imatinib in the presence of mesenchymal stromal cells retained the ability to engraft into NOD/SCID mice. We observed that chronic myeloid leukemia cells and mesenchymal stromal cells express functional levels of CXCR4 and CXCL12, respectively. Finally, the CXCR4 antagonist, AMD3100 restored apoptosis by imatinib and the susceptibility of the SCID leukemia repopulating cells to the tyrosine kinase inhibitor. ConclusionsHuman mesenchymal stromal cells mediate protection of chronic myeloid leukemia cells from imatinib-induced apoptosis. Disruption of the CXCL12/CXCR4 axis restores, at least in part, the leukemic cells' sensitivity to imatinib. The combination of anti-CXCR4 antagonists with tyrosine kinase inhibitors may represent a powerful approach to the treatment of chronic myeloid leukemia.

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Long-term culture of infant leukemia cells: Dependence upon stromal cells from the bone marrow and bilineage differentiation

Cited by 36 publications

References 19 publications

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

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

The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL

Bone marrow mesenchymal stromal cells non-selectively protect chronic myeloid leukemia cells from imatinib-induced apoptosis via the CXCR4/CXCL12 axis

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