Table 1.
Cytokines and growth factors supporting or inhibiting AML cells.
| Cytokine | Expression in AML patients compared to healthy individuals | Physiologic function | Function ex vivo in AML cell culture |
|---|---|---|---|
| G-CSF | Not determined | Hematopoietic growth factor | Supports AML cell proliferation and clonogenicity (45–48) |
| GM-CSF | Elevated PB plasma levels and unchanged BM levels (42, 49) | Hematopoietic growth factor | Supports AML cell growth and self-renewal (44, 45, 50) |
| IFN-α | Not determined | Anti-/Pro-inflammatory cytokine | Reduces AML cell proliferation and IL-1, IL-6, GM-CSF expression (51, 52) |
| IFN-γ | Unchanged PB levels and reduced BM levels (39, 53) | Pro-inflammatory cytokine | Reduces AML cell proliferation and survival; increases spontaneous clonogenicity of AML cells (54, 55) |
| IL-1Ra | Elevated PB and reduced BM serum levels (42, 56) | Anti-inflammatory cytokine | Reduces AML cell proliferation (57, 58) |
| IL-1β | Unchanged or elevated PB and unchanged BM levels (39, 41, 42) | Pro-inflammatory cytokine | Supports AML cell proliferation and survival; increases GM-CSF, IL-6 and TNF expression (41, 45, 50, 51, 59, 60) |
| IL-3 | Elevated PB levels (43) | Pro-inflammatory cytokine | Supports AML cell proliferation and self-renewal (45, 47, 61–63) |
| IL-4 | Elevated PB levels in patients > 65 years (39, 53) | Anti-inflammatory cytokine | Inhibits IL-1- and HGF-induced AML cell proliferation (60, 64, 65) |
| IL-6 | Elevated plasma levels (39, 53, 66) | Pro-inflammatory cytokine | Partially supports AML cell proliferation (45, 48, 67–71). |
| IL-8 | Elevated PB and BM levels (39, 44, 66, 72) | Chemoattractant cytokine (chemokine) | Not determined |
| IL-10 | Elevated PB levels (39, 53, 56, 73) | Anti-inflammatory cytokine | Inhibits AML cell proliferation; reduces IL-1α, IL-1β, IL-6, GM-CSF and TNF-α expression (74–76) |
| IL-12p70 | Elevated PB levels in patients > 65 years (39) | Pro-inflammatory cytokine | Inhibits AML cell-induced angiogenesis; supports T cell-mediated cytotoxicity and possibly AML tumor growth (77–79) |
| IL-27 | Elevated PB and BM levels (40) | Anti-inflammatory cytokine | Not determined |
| IL-35 | Elevated PB and BM levels (40, 80, 81) | Anti-inflammatory cytokine | Supports AML cell proliferation and survival; promotes Treg function (80) |
| Osteopontin | Elevated PB and BM levels (44, 82, 83) | Matrix glycoprotein with pro-inflammatory cytokine properties | Supports AML cell self-renewal, proliferation and survival (84) |
| SCF | Elevated PB and BM levels (42) | Hematopoietic growth factor | Supports AML cell proliferation and survival (85–87) |
| TGF-β | Reduced PB and BM levels (39, 53) | Anti-inflammatory cytokine | Inhibits AML cell proliferation and survival (88–90) |
| TNF-α | Elevated PB levels (39, 44, 56, 66) | Pro-inflammatory cytokine | Supports AML cell chemoresistance and maintains proliferating LSCs (91) |
| TRAIL | Reduced PB levels (44) | Pro-inflammatory cytokine | Not determined |
| CXCL12 | Reduced expression in AML blasts (92–94) | Chemoattractant cytokine (chemokine) | Promotes AML cell growth, survival, chemoresistance and adhesion (95–98) |
Importantly, not all patient-derived AML cells or cell lines respond to HGF and cytokine treatment equally well. These observations reflect AML heterogeneity and suggest the presence of leukemic cell subpopulations. PB: peripheral blood; BM: bone marrow.