Aryl hydrocarbon receptor (AHR) is a novel druggable pathway controlling malignant progenitor proliferation in chronic myeloid leukemia (CML)

Abstract

Aryl Hydrocarbon Receptor (AHR) is an ubiquitous basic helix-loop-helix transcription factor, which is ligand-activated and involved in numerous biological processes including cell division, cell quiescence and inflammation. It has been shown that AHR is involved in normal hematopoietic progenitor proliferation in human cells. In addition, loss of AHR in knockout mice is accompanied by a myeloproliferative syndrome-like disease, suggesting a role of AHR in hematopoietic stem cell (HSC) maintenance. To study the potential role of AHR pathway in CML progenitors and stem cells, we have first evaluated the expression of AHR in UT-7 cell line expressing BCR-ABL. AHR expression was highly reduced in UT-7 cell expressing BCR-ABL as compared to controls. AHR transcript levels, quantified in primary peripheral blood CML cells at diagnosis (n = 31 patients) were found to be significantly reduced compared to healthy controls (n = 15). The use of StemRegenin (SR1), an AHR antagonist, induced a marked expansion of total leukemic cells and leukemic CD34+ cells by about 4- and 10-fold respectively. SR1-treated CML CD34+ cells generated more colony-forming cells and long-term culture initiating cell (LTC-IC)–derived progenitors as compared to non-SR1-treated counterparts. Conversely, treatment of CML CD34+ cells with FICZ, a natural agonist of AHR, induced a 3-fold decrease in the number of CD34+ cells in culture after 7 days. Moreover, a 4-day FICZ treatment was sufficient to significantly reduce the clonogenic potential of CML CD34+ cells and this effect was synergized by Imatinib and Dasatinib treatments. Similarly, a 3-day FICZ treatment contributed to hinder significantly the number of LTC-IC-derived progenitors without synergistic effect with Imatinib. The analysis of molecular circuitry of AHR signaling in CML showed a transcriptional signature in CML derived CD34+ CD38- primitive cells with either low or high levels of AHR, with an upregulation of myeloid genes involved in differentiation in the “AHR low” fraction and an upregulation of genes involved in stem cell maintenance in the “AHR high” fraction. In conclusion, these findings demonstrate for the first time that down-regulation of AHR expression, a major cell cycle regulator, is involved in the myeloproliferative phenotype associated with CML. AHR agonists inhibit clonogenic and LTC-IC-derived progenitor growth and they could be used in leukemic stem cell targeting in CML.

The therapeutic potential of targeting tryptophan catabolism in cancer

“…Currently, the AHR inhibitors CH223191 and StemRegenin 1 (SR1) are commonly used to study AHR-activation mediated effects. 1 , 55 , 66 , 97 , 198 – 200 CH223191 and SR1 exert their inhibitory effect through direct binding to AHR. 201 , 202 AHR inhibitors are currently being developed by multiple pharmaceutical companies including Kyn Therapeutics, 203 Hercules Pharmaceuticals, 103 Phenex Pharmaceuticals, 197 Ideaya Biosciences 204 and Bayer AG.…”

AhR and Cancer: From Gene Profiling to Targeted Therapy

“…Accordingly, AhR expression was shown to be associated with a poor prognosis in glioma [ 20 ]. On the contrary, AhR expression was significantly lower in primary peripheral blood chronic myeloid leukemia (CML) cells than in healthy controls supporting the notion of cell specific functions of AhR [ 21 ].…”

“…FICZ has also been shown to have anti-proliferative and anti-migratory properties on LNCaP cells, a cell line derived from androgen-sensitive human prostate adenocarcinoma cells [ 68 ]. Finally, FICZ significantly reduces the clonogenic potential of CD34-positive cells in chronic myeloid leukemia (CML) [ 21 ].…”

Cysteine‐rich protein 61 regulates the chemosensitivity of chronic myeloid leukemia to imatinib mesylate through the nuclear factor kappa B/Bcl‐2 pathway

“…The CML K562 cell line and KCL22 cell line were maintained in RPMI 1640 medium (HyClone, Logan, UT, USA) supplemented with 10% FBS (Gibco, Carlsbad, CA, USA) and 10% penicillin/streptomycin in a 37°C incubator supplied with 5% CO 2 . Primary leukemic cells from three patients with chronic‐phase CML were isolated using Ficoll gradient as described previously and then were grown in RPMI 1640 medium supplemented with 10% FBS and antibiotic/antimycotic solution. The research methods conformed to the standards stipulated in the Declaration of Helsinki and were approved by the Institutional Medical Ethics Review Board of the Fujian Medical University Union Hospital.…”