IL-1 signalling key for leukaemic stem cell maintenance in CML
medwireNews: Preclinical research suggests that interleukin (IL)-1–mediated inflammatory signalling is crucial for the maintenance of chronic myeloid leukaemia (CML) stem cells persisting after treatment with tyrosine kinase inhibitors (TKIs).
The findings “provide a strong rationale for further exploration of anti-IL-1 strategies to enhance [leukaemia stem cells] elimination in CML”, say Ravi Bhatia, from the University of Alabama at Birmingham in the USA, and team.
They showed previously that IL-1 expression is elevated in bone marrow isolated from transgenic mice expressing BCR–ABL.
And in the current study, the team found that the expression of certain IL-1 receptor components – specifically, IL-1 receptor Type I and IL-1 receptor accessory protein – were also increased on human CML stem cells relative to normal CD34+CD38-CD90+ stem cells.
Furthermore, induction with IL-1α led to elevated expression, as assessed by flow cytometry, of downstream components of the IL-1 signalling pathway, such as p-NF-κB, in CML stem cells alone.
Bhatia et al also evaluated the effects of blocking IL-1 signalling. After mixing murine CML and normal stem cells in an equivalent ratio, they cultured the mixture in bone marrow isolated from transgenic CML mice, either with or without the recombinant IL-1 receptor antagonist (IL-1RA). Treatment with IL-1RA significantly reduced the proportion of CML to normal stem cells, suggesting that IL-1 blockade inhibits the growth of CML stem cells.
Moreover, the effects of the TKI nilotinib were enhanced when combined with IL-1RA. For instance, exposure to nilotinib alone or IL-1RA alone inhibited the growth and proliferation of CML stem cells, but the effect was strongest with the combination.
The researchers believe that targeting IL-1 signalling to eliminate persistent leukaemic stem cells could help TKI-treated CML patients to achieve treatment-free remission.
Several strategies to limit IL-1 activity are already approved for treating chronic inflammatory disorders and include the IL1-RA anakinra, neutralizing antibodies against IL-1β and a soluble IL-1 receptor, they write in Blood.
medwireNews is an independent medical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2016