Aryl hydrocarbon receptor (AHR) is a novel druggable pathway controlling malignant progenitor proliferation in chronic myeloid leukemia (CML)
Aryl Hydrocarbon Receptor (AHR) is definitely an ubiquitous fundamental helix-loop-helix transcription factor, that is ligand-activated and involved with numerous biological processes including cell division, cell quiescence and inflammation. It’s been proven that AHR is involved with normal hematopoietic progenitor proliferation in human cells. Additionally, lack of AHR in knockout rodents is supported with a myeloproliferative syndrome-like disease, suggesting a job of AHR in hematopoietic stem cell (HSC) maintenance. To review the possibility role of AHR path in CML progenitors and stem cells, we’ve 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 when compared with controls. AHR transcript levels, quantified in primary peripheral bloodstream CML cells at diagnosis (n = 31 patients) were discovered to be considerably reduced when compared with healthy controls (n = 15). Using StemRegenin 1 (SR1), an AHR antagonist, caused reasonable growth of total leukemic cells and leukemic CD34 cells by about 4- and 10-fold correspondingly. SR1-treated CML CD34 cells generated more colony-developing cells and lengthy-term culture initiating cell (LTC-IC)-derived progenitors when compared with non-SR1-treated counterparts. On the other hand, management of CML CD34 cells with FICZ, an all natural agonist of AHR, caused a 3-fold reduction in the amount of CD34 cells in culture after seven days. Furthermore, a 4-day FICZ treatment was sufficient to considerably lessen the clonogenic potential of CML CD34 cells which effect was synergized by Imatinib and Dasatinib treatments. Similarly, a 3-day FICZ treatment led to hinder considerably the amount of LTC-IC-derived progenitors without synergistic effect with Imatinib. Case study of molecular circuitry of AHR signaling in CML demonstrated a transcriptional signature in CML derived CD34 CD38- primitive cells with either low or high amounts of AHR, by having an upregulation of myeloid genes involved with differentiation within the “AHR low” fraction as well as an upregulation of genes involved with stem cell maintenance within the “AHR high” fraction. To conclude, these bits of information demonstrate the very first time that lower-regulating AHR expression, a significant cell cycle regulator, is active in the myeloproliferative phenotype connected with CML. AHR agonists hinder clonogenic and LTC-IC-derived progenitor growth and they may be utilized in leukemic stem cell targeting in CML.