German researchers have identified factors which may contribute to bone marrow failure in acute myeloid leukaemia (AML). The research, carried out at Heinrich-Heine-University Düsseldorf, shows that blocking TGFβ1 may have the potential to improve haematopoiesis in AML patients.
Dr Thomas Schroeder and his team investigated what role molecules secreted by leukaemic cells might play in inhibiting the growth of healthy hematopoietic stem and progenitor cells (HSPCs).
He said: “Experiments using conditioned media (CM) from AML cells to address secretory mechanisms have been performed before, but mainly in mice.
“In order to gain new insights into how this plays out in humans, we focused on the interaction between leukemic cells and healthy HSPC using an in vitro system modelling the in vivo situation of bone marrow infiltration by AML cells.”
AML cell lines, and cells donated by patients, were grown in cell culture medium. Then, healthy CD34+ haematopoietic stem cells were exposed to the supernatant (liquid that the cells had been cultured in) from these leukaemia cells.
“Our findings revealed that exposure to AML-derived supernatants significantly inhibited proliferation, cell cycling, colony formation and differentiation of healthy CD34+ HSPC. Further experiments determined that leukemic cells induce functional inhibition of healthy HSPC, at least in part through TGFβ1.”
The team showed that blocking the TGFβ1 pathway with the TGFβ1 inhibitor SD208 could partially reverse this effect. “Our data indicate this could be a promising approach to improve haematopoiesis in AML patients," Dr Schroeder said.
Jäger P, Geyh S, Twarock S, Cadeddu RP, Rabes P, Koch A, Maus U, Hesper T, Zilkens C, Rautenberg C, Bormann F, Köhrer K, Petzsch P, Wieczorek D, Betz B, Surowy H, Hildebrandt B, Germing U, Kobbe G, Haas R, Schroeder T. (2021) “Acute myeloid leukemia-induced functional inhibition of healthy CD34+ hematopoietic stem and progenitor cells.” Stem Cells, doi: 10.1002/stem.3387
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