Osteoblasts increase proliferation and release of pro-angiogenic interleukin 8 by native human acute myelogenous leukemia blasts.

BACKGROUND AND OBJECTIVES Interactions between acute myelogenous leukemia (AML) blasts and non-leukemic cells in the bone marrow seem to be important for both disease development and susceptibility to chemotherapy. Recent studies have focused on the endothelial cells, but other non-leukemic cells may also be involved. In the present study we investigated how osteoblasts affect native human AML blasts. DESIGN AND METHODS AML cells were derived from a large group of consecutive patients. The AML blasts and osteoblastic sarcoma cell lines (Cal72, SJSA-1) were incubated together in different chambers separated by a semipermeable membrane. We investigated effects of co-culture on proliferation, apoptosis and cytokine release. RESULTS The cross-talk between these two cell populations, achieved via release of soluble mediators, resulted in increased AML blast proliferation, including increased proliferation of clonogenic progenitors, but did not affect spontaneous in vitro apoptosis. Both interleukin (IL) 1-b and granulocyte-macrophage colony-stimulating factor were involved in this growth-enhancing cross-talk, and normal osteoblasts could also increase the AML blast proliferation. Furthermore, co-culture of AML blasts with osteoblastic sarcoma cells as well as normal osteoblasts increased the levels of the pro-angiogenic mediator IL8. INTERPRETATION AND CONCLUSIONS Our in vitro results suggest that the release of soluble mediators by osteoblasts supports leukemic hematopoiesis through two major mechanisms: (i) direct enhancement of AML blast proliferation; and (ii) enhanced angiogenesis caused by increased IL8 levels.

[1]  Ø. Bruserud,et al.  The angioregulatory phenotype of native human acute myelogenous leukemia cells: influence of karyotype, Flt3 abnormalities and differentiation status , 2003, European journal of haematology.

[2]  J. Burger,et al.  CXCR4 chemokine receptors (CD184) and α4β1 integrins mediate spontaneous migration of human CD34+ progenitors and acute myeloid leukaemia cells beneath marrow stromal cells (pseudoemperipolesis) , 2003, British journal of haematology.

[3]  Ø. Bruserud,et al.  In vitro culture of human acute lymphoblastic leukemia (ALL) cells in serum-free media; a comparison of native ALL blasts, ALL cell lines and virus-transformed B cell lines. , 2003, Leukemia research.

[4]  D. F. Far,et al.  CAL72: a human osteosarcoma cell line with unique effects on hematopoietic cells , 2003, European journal of haematology.

[5]  D. Steensma,et al.  Flow cytometric methods for detection and quantification of apoptosis. , 2003, Methods in molecular medicine.

[6]  Ø. Bruserud,et al.  Flt3-mediated signaling in human acute myelogenous leukemia (AML) blasts: a functional characterization of Flt3-ligand effects in AML cell populations with and without genetic Flt3 abnormalities. , 2003, Haematologica.

[7]  E. Estey,et al.  Plasma vascular endothelial growth factor levels have prognostic significance in patients with acute myeloid leukemia but not in patients with myelodysplastic syndromes , 2002, Cancer.

[8]  G. Ehninger,et al.  Analysis of Flt3-activating Mutations in 979 Patients with Acute Myelogenous Leukemia: Association with Fab Subtypes and Identification of Subgroups with Poor Prognosis , 2022 .

[9]  Yu Shen,et al.  Clinical significance of plasma endostatin in acute myeloid leukemia/myelodysplastic syndrome , 2002, Cancer.

[10]  M. Konopleva,et al.  Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins , 2002, Leukemia.

[11]  Ø. Bruserud,et al.  Leptin in human acute myelogenous leukemia: studies of in vivo levels and in vitro effects on native functional leukemia blasts. , 2002, Haematologica.

[12]  W. Kamps,et al.  A possible role for spontaneous interleukin-8 production by acute myeloid leukemic cells in angiogenesis related processes: work in progress. , 2001, Medical and pediatric oncology.

[13]  M. Caligiuri,et al.  Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. , 2001, Cancer research.

[14]  F. Appelbaum,et al.  Acute myeloid leukemia cells are protected from spontaneous and drug-induced apoptosis by direct contact with a human bone marrow stromal cell line (HS-5). , 2001, Experimental hematology.

[15]  Ø. Bruserud,et al.  New Strategies in the Treatment of Acute Myelogenous Leukemia (AML): In Vitro Culture of AML Cells—The Present Use in Experimental Studies and the Possible Importance for Future Therapeutic Approaches , 2001, Stem cells.

[16]  B. Gjertsen,et al.  In vitro culture of human acute myelogenous leukemia (AML) cells in serum-free media: studies of native AML blasts and AML cell lines. , 2000, Journal of hematotherapy & stem cell research.

[17]  G. Karsenty,et al.  The osteoblast: a sophisticated fibroblast under central surveillance. , 2000, Science.

[18]  W. Berdel,et al.  Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia. , 2000, Blood.

[19]  C. Figdor,et al.  Molecular analysis of the hematopoiesis supporting osteoblastic cell line U2-OS. , 2000, Experimental hematology.

[20]  Matthews,et al.  Human osteoblast‐like cells and osteosarcoma cell lines synthesize macrophage inhibitory protein 1α in response to interleukin 1β and tumour necrosis factor α stimulation in vitro , 2000 .

[21]  E. Estey,et al.  Cellular vascular endothelial growth factor is a predictor of outcome in patients with acute myeloid leukemia. , 1999, Blood.

[22]  R. Gray,et al.  A simple, robust, validated and highly predictive index for the determination of risk‐directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial , 1999, British journal of haematology.

[23]  A. Chompret,et al.  Establishment, characterisation and partial cytokine expression profile of a new human osteosarcoma cell line (CAL 72) , 1999, International journal of cancer.

[24]  O. Bruserud,et al.  In vitro culture of acute myelogenous leukemia blasts: a comparison of four different culture media. , 1999, Journal of hematotherapy.

[25]  J. Downing,et al.  Acute myeloid leukemia. , 1999, The New England journal of medicine.

[26]  R. Taichman,et al.  The Role of Osteoblasts in the Hematopoietic Microenvironment , 1998, Stem cells.

[27]  C. Bloomfield,et al.  Clinical significance of cytogenetics in acute myeloid leukemia. , 1997, Seminars in oncology.

[28]  E. Paietta.  Proposals for the immunological classification of acute leukemias. , 1995, Leukemia.

[29]  C Haanen,et al.  A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. , 1995, Journal of immunological methods.

[30]  W. Beecken,et al.  Chimaeric cultures of human marrow stroma and murine leukaemia cells: evidence for abnormalities in the haemopoietic microenvironment in myeloid malignancies and other infiltrating marrow disorders , 1995, British journal of haematology.

[31]  K. Bradstock,et al.  Interaction of acute leukemia cells with the bone marrow microenvironment: implications for control of minimal residual disease. , 1995, Leukemia & lymphoma.

[32]  Ø. Bruserud,et al.  Effects of interleukin 10 on blast cells derived from patients with acute myelogenous leukemia. , 1995, Leukemia.

[33]  L. Bendall,et al.  Bone marrow adherent layers inhibit apoptosis of acute myeloid leukemia cells. , 1994, Experimental hematology.

[34]  M. Chilosi,et al.  IL-8 mRNA expression and IL-8 production by acute myeloid leukemia cells. , 1993, Leukemia.

[35]  O. Bruserud.  Effect of dipyridamole, theophyllamine and verapamil on spontaneous in vitro proliferation of myelogenous leukaemia cells. , 1992, Acta oncologica.

[36]  T. Dexter,et al.  Heparan sulphate bound growth factors: a mechanism for stromal cell mediated haemopoiesis , 1988, Nature.