The role of soluble growth factors in inducing transient growth and clonal extinction of stroma cell dependent erythroblastic leukemia cells

Itoh, Katsuhiko; Friel, Jutta; Laker, Christine; Zeller, W.; Just, Ursula; Bittner, Sebastian; Nibbs, Robert J. B.; Harrison, Paul R.; Nishikawa, Satomi; Mori, Kazuhiro; Ostertag, Wolfram

doi:10.1038/sj.leu.2400787

Cited by 18 publications

(11 citation statements)

References 4 publications

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“…[63][64][65][66][67] We investigated the possibility that stromal cells maintain the viability of myeloid leukemic cells by regulating Bcl-2 expression and found that after the induction of apoptosis, Bcl-2 mRNA levels were increased in stroma-supported HL-60 cells compared to control cells. These data are in agreement with those obtained from several studies showing that Bcl-2 is up-regulated in ELM-D, 14 Myl-D7 15 and DA-1 cells 68 in contact with MS-5 cells. Recently, it was demonstrated that Bcl-2 not only inhibits apoptosis, but also restrains cell-cycle entry [69][70][71] and that these two functions can be genetically dissociated.…”

Section: Figuresupporting

confidence: 83%

“…Although the nature of the stromal cellinduced changes in leukemic cells is poorly understood, several studies have suggested that the anti-apoptotic proteins may confer survival advantage on stroma-supported hematopoietic cells. [13][14][15] We therefore studied the role of stromal cells on the survival of leukemic cells using the murine stromal cell line MS-5, 16 which was shown to support primitive human progenitors [17][18][19] and a factor-dependent human leukemic cell line. 20 We especially focused on the role of Bcl-2 family proteins in protecting AML cells from ara-C-induced apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins

Konopleva

Konoplev²,

Hu³

et al. 2002

Leukemia

356

290

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The aim of this study was to study interactions between stromal bone marrow microenvironment and leukemic cells. We tested the hypothesis that stromal cells prevent apoptosis of AML cells by up-regulating anti-apoptotic proteins in leukemic blasts. In HL-60 and NB-4 cells, serum deprivation-and ara-Cinduced apoptosis was diminished when cells were cocultured with murine MS-5 stromal cells (P Ͻ 0.02). This effect was reproduced with conditioned medium from MS-5 cells. Cocultivation with stromal cells induced Bcl-2 expression levels, both by PCR analysis and flow cytometry. In primary AML (n = 14), ara-C-induced apoptosis was significantly lower in cells cocultured with MS-5 cells than in controls (P Ͻ 0.001). This effect was partially preserved when leukemic cells were separated from stromal cells by a microporous insert (in 5/9 samples, P = 0.04). In addition, Bcl-2 levels were significantly higher in stroma-supported than in control CD34+ AML cells (P Ͻ 0.01). Bcl-X L levels were higher in 5/7 samples grown on stromal layers. Of note, in AML patients resistant to induction chemotherapy (n = 6), Bcl-2 increased significantly after cultivation with stromal cells, but no such increase was noted in cells from chemotherapy-sensitive patients. In conclusion, MS-5 stromal cells prevented apoptosis in HL-60 cells and in primary AML blasts via modulation of Bcl-2 family proteins. The observed association of high Bcl-2 expression in stroma-supported AML blasts in vitro with resistance to chemotherapy in vivo suggests that the same mechanisms may be operational in vivo.

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Section: Figuresupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins

Konopleva

Konoplev²,

Hu³

et al. 2002

Leukemia

356

290

View full text Add to dashboard Cite

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“…The role of the first was shown by studies on W and Sl mutant mice lacking a functional c-kit receptor gene and the gene encoding the ligand SCF, respectively (Russel, 1979;Silvers, 1979). We and others have shown, that interaction of SCF with c-kit is also functional in coculture systems of different hematopoietic cell lines with stroma cells (Toksoz et al, 1992;Itoh et al, 1997;Heberlein et al, 1999;Friel et al, 2002).…”

Section: Discussionmentioning

confidence: 93%

“…At present, only the stem cell factor (SCF)/SCF receptor and the flt-3 ligand/flt-3 receptor systems are known to be involved in regulating direct hematopoietic and stromal cell contact (Itoh et al, 1997;Heberlein et al, 1999), although several other soluble factors are secreted by stroma. Interestingly, hematopoietic stem and progenitor cells can also be maintained on SCFnegative stroma, indicating that there are SCF-independent mechanisms for growth stimulation (Sutherland et al, 1993;O'Prey et al, 1998;Friel et al, 2002).…”

mentioning

confidence: 98%

Involvement of CSF‐1 in generating a stroma‐independent hematopoietic stem cell line

Heberlein¹,

Friel²,

Itoh³

et al. 2005

Journal Cellular Physiology

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The hematopoietic stem cell line, Myl-D7, is maintained by a self-renewing stem cell population that spontaneously generates myeloid, lymphoid, and erythroid progeny. MS-5 stromal cells are necessary for the growth of Myl-D7 cells. One component of the Myl-D7 cells proliferation activity released by MS-5 stromal cells was enriched by Q sepharose fractionation and shown to be colony stimulating factor-1 (CSF-1) by Western blotting, BAC1.2F5 cell bioassay and inhibition of Myl-D7 proliferation by CSF-1 antibody. The requirement of Myl-D7 cells for CSF-1 was also demonstrated independently by selecting for rare, stroma-independent Myl-D7 mutant clones able to grow without stroma and additional factors. Eighty-nine stroma-independent mutant clones were obtained and belonged to two classes. The majority of mutants did not secrete any growth promoting activity. The second, rarer class of mutants releases a factor that stimulates proliferation/survival for up to several months and approximately half of the secretors express high levels of CSF-1 mRNA. Wild type Myl-D7 grown with supernatants from the secretor cells retained the stem cell phenotype. These data suggest that CSF-1 may act as a key factor in stroma-regulated hematopoiesis and cell-cell interaction.

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“…The majority of studies investigating signaling pathways activated by c-Kit have been performed with sSLF. However, there is evidence to suggest that the soluble and membrane-bound forms of SLF stimulate qualitatively different responses in c-Kit-positive cells [23][24][25][26][27][28][29]. Using the 32D murine myelomonocytic cell line model, we recently demonstrated that PLC-g activation, but not PI3-kinase activation, was essential for mSLF to support c-Kitpositive 32D cells in vitro and in vivo [30].…”

Section: Cmls Cellular and Molecular Life Sciencesmentioning

confidence: 99%

Mast cells stimulated by membrane-bound, but not soluble, steel factor are dependent on phospholipase C activation

Trieselmann¹,

Soboloff²,

Berger³

2003

Cellular and Molecular Life Sciences (CMLS)

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The steel factor (SLF) and c-Kit growth factor/receptor pair are key molecules governing mast cell development and survival. SLF is expressed on stromal cells as a membrane-bound molecule (mSLF) which can be cleaved by proteases to release a soluble form (sSLF). We investigated the importance of phospholipase C (PLC) activation in mast cells stimulated by sSLF and mSLF. PLC antagonists U73122, neomycin sulfate and oleic acid inhibited mast cell thymidine incorporation stimulated by mSLF, but not by sSLF. These antagonists suppressed sSLF-induced Ca2+ transients but did not significantly interfere with c-Kit phosphorylation or PLC-gamma2 recruitment. p85, the regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase), was found to be efficiently recruited to c-Kit following stimulation by sSLF or mSLF. However PKB/Akt, a kinase activated by PI3-kinase products, was phosphorylated following sSLF stimulation, but not with mSLF. Taken together, these studies demonstrate the importance of PLC activation by mSLF in supporting mast cells.

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The role of soluble growth factors in inducing transient growth and clonal extinction of stroma cell dependent erythroblastic leukemia cells

Cited by 18 publications

References 4 publications

Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins

Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins

Involvement of CSF‐1 in generating a stroma‐independent hematopoietic stem cell line

Mast cells stimulated by membrane-bound, but not soluble, steel factor are dependent on phospholipase C activation

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