Infliximab therapy together with tyrosine kinase inhibition targets leukemic stem cells in chronic myeloid leukemia

Oliver Herrmann,
Maja Kim Kuepper,
Marlena Bütow,
Ivan G. Costa,
Iris Appelmann,
Fabian Beier,
Tom Luedde,
Till Braunschweig,
Steffen Koschmieder,
Tim H. Brümmendorf and
Mirle SchemionekEmail author View ORCID ID profile

BMC Cancer201919:658

https://doi.org/10.1186/s12885-019-5871-2

Received: 26 April 2018
Accepted: 24 June 2019
Published: 4 July 2019

Open Peer Review reports

Abstract

Background

Expression of Bcr-Abl in hematopoietic stem cells is sufficient to cause chronic myeloid leukemia (CML) and tyrosine kinase inhibitors (TKI) induce molecular remission in the majority of CML patients. However, the disease driving stem cell population is not fully targeted by TKI therapy, and leukemic stem cells (LSC) capable of re-inducing the disease can persist. Single-cell RNA-sequencing technology recently identified an enriched inflammatory gene signature with TNFα and TGFβ being activated in TKI persisting quiescent LSC. Here, we studied the effects of human TNFα antibody infliximab (IFX), which has been shown to induce anti-inflammatory effects in mice, combined with TKI treatment on LSC function.

Methods

We first performed GSEA-pathway analysis using our microarray data of murine LSK cells (lin−; Sca-1+; c-kit+) from the SCLtTA/Bcr-Abl CML transgenic mouse model. Bcr-Abl positive cell lines were generated by retroviral transduction. Clonogenic potential was assessed by CFU (colony forming unit). CML mice were treated with nilotinib or nilotinib plus infliximab, and serial transplantation experiments were performed.

Results

Likewise to human CML, TNFα signaling was specifically active in murine CML stem cells, and ectopic expression of Bcr-Abl in murine and human progenitor cell lines induced TNFα expression. In vitro exposure to human (IFX) or murine (MP6-XT22) TNFα antibody reduced clonogenic growth of CML cells. Interestingly, TNFα antibody treatment enhanced TKI-induced effects on immature cells in vitro. Additionally, in transplant and serial transplant experiments, using our transgenic CML mouse model, we could subsequently show that IFX therapy boosted TKI-induced effects and further reduced the proportion of malignant stem cells in vivo.

Conclusion

TNFα signaling is induced in CML stem cells, and anti-inflammatory therapy enhances TKI-induced decline of LSC, confirming that successful targeting of persisting CML stem cells can be enhanced by addressing their malignant microenvironment simultaneously.