Interleukin-6 and granulocyte-macrophage colony-stimulating factor are candidate growth factors for chronic myelomonocytic leukemia cells

Abstract

Previous studies suggest that malignant cells from some patients with myeloid leukemias produce colony-stimulating factors (CSFs) that can function as autocrine growth factors in vitro. We have examined the roles of interleukin-6 (IL-6) and granulocyte-macrophage CSF (GM-CSF) in the proliferation of myeloid leukemia cells. IL-6 activity was assessed in conditioned medium (CM) from myeloid leukemia cell cultures or cell lysates using IL-6-dependent KD83 and 7TD1 murine cell lines. Media conditioned by cells from patients with chronic myelomonocytic leukemia (CMMoL), but not by normal monocytes, chronic myelogenous leukemia (CML), or acute myelogenous leukemia (AML) cells, contained substantial levels (50 to 1,000 U/10(6) cells) of IL-6. The IL-6 content of CM correlated directly with donor peripheral blood WBC count. CM from two of five CMMoL samples also contained greater than 350 pg/mL GM-CSF. Moreover, CMMoL cells spontaneously formed colonies in semisolid medium. CMMoL colony formation could be partially inhibited by antibodies to IL-6 or GM-CSF, whereas combination of these antibodies gave additive, and nearly complete (greater than 93%), inhibition of spontaneous colony formation. Cell lysates from uncultured CMMoL cells from one patient contained abundant GM-CSF protein but no detectable IL-6. These data suggest that IL-6 and GM-CSF act in vitro as autocrine growth factors for CMMoL cells, and that CMMoL cells in vivo may represent a GM-CSF-dependent autocrine growth system.

BCR-ABL promotes hematopoietic stem and progenitor cell formation in embryonic stem cells

“…It is generally assumed that the constitutive tyrosine kinase activity of BCR-ABL oncoprotein promotes CML cell growth and cell survival leading to relative cytokine independence 59 . Conversely, several cytokines have been reported to expand primitive CML cells including IL-6 [60][61][62][63] . IL-6 is highly expressed in CML patients 64 and its expression is associated with poor prognosis 65,66 .…”

Significance of hypergammaglobulinemia in patients with chronic myelomonocytic leukemia

“…There is clear evidence in the literature that IL‑6 is one of the main stimulatory factors of IgG production [ 28 , 29 ]. On the other hand, it has been shown that CMML cells can produce IL‑6 in vitro and stimulate CMML cell growth in an autocrine manner [ 30 ]. One attractive hypothesis of our exploratory findings could be that IL‑6 may provide a common basis for hypergammaglobulinemia and the adverse outcome in these patients.…”