title: Differences in gene expression and alterations in cell cycle of acute myeloid leukemia cell lines after treatment with JAK inhibitors.
abstract: Janus kinase (JAK) inhibitors are a promising treatment strategy in several hematological malignancies and autoimmune diseases. A number of inhibitors are in clinical development, and two have already reached the market. Unfortunately, all of them are burdened with different toxicity profiles. To check if the JAK inhibitors of different selectivity evoke different responses on JAK2-dependent and independent cells, we have used three acute myeloid leukemia cell lines with confirmed JAK2 mutation status. We have found that JAK inhibitors exert distinct effect on the expression of BCLXL, CCND1 and c-MYC genes, regulated by JAK pathway, in JAK2 wild type cells in comparison to JAK2 V617F-positive cell lines. Moreover, cell cycle analysis showed that inhibitors alter the cycle by arresting cells in different phases. Our results suggest that observed effect of JAK2 inhibitors on transcription and cell cycle level in different cell lines are associated not with activity within JAK family, but presumably with other off-target activities.
authors: Department of Medical Biotechnology, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland; Innovative Drugs Research & Development Department, Celon Pharma S.A., Mokra 41A, Kielpin, 05-092 Lomianki, Poland. Electronic address: pawel.gunerka@celonpharma.com.
authors: Pawel
authors: P
authors: Gunerka
authors: Innovative Drugs Research & Development Department, Celon Pharma S.A., Mokra 41A, Kielpin, 05-092 Lomianki, Poland.
authors: Barbara
authors: B
authors: Dymek
authors: Innovative Drugs Research & Development Department, Celon Pharma S.A., Mokra 41A, Kielpin, 05-092 Lomianki, Poland.
authors: Aleksandra
authors: A
authors: Stanczak
authors: Innovative Drugs Research & Development Department, Celon Pharma S.A., Mokra 41A, Kielpin, 05-092 Lomianki, Poland; Postgraduate School of Molecular Medicine, Zwirki i Wigury 61, 02-091 Warsaw, Poland.
authors: Anna
authors: A
authors: Bujak
authors: Innovative Drugs Research & Development Department, Celon Pharma S.A., Mokra 41A, Kielpin, 05-092 Lomianki, Poland; Postgraduate School of Molecular Medicine, Zwirki i Wigury 61, 02-091 Warsaw, Poland.
authors: Paulina
authors: P
authors: Grygielewicz
authors: Innovative Drugs Research & Development Department, Celon Pharma S.A., Mokra 41A, Kielpin, 05-092 Lomianki, Poland.
authors: Pawel
authors: P
authors: Turowski
authors: Innovative Drugs Research & Development Department, Celon Pharma S.A., Mokra 41A, Kielpin, 05-092 Lomianki, Poland.
authors: Karolina
authors: K
authors: Dzwonek
authors: Innovative Drugs Research & Development Department, Celon Pharma S.A., Mokra 41A, Kielpin, 05-092 Lomianki, Poland.
authors: Monika
authors: M
authors: Lamparska-Przybysz
authors: Department of Medical Biotechnology, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland.
authors: Tadeusz
authors: T
authors: Pietrucha
authors: Innovative Drugs Research & Development Department, Celon Pharma S.A., Mokra 41A, Kielpin, 05-092 Lomianki, Poland.
authors: Maciej
authors: M
authors: Wieczorek
mesh_terms: D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology; D009570:Nitriles; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D051020:bcl-X Protein / Q000235:genetics; D000096926:Benzenesulfonamides
chemical_list: D019938:Cyclin D1; D007093:Imidazoles; D053612:Janus Kinases; D009570:Nitriles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011724:Pyridazines; D011743:Pyrimidines; D011758:Pyrroles; D011759:Pyrrolidines; D013449:Sulfonamides; D051020:bcl-X Protein; C530104:CCND1 protein, human; C581039:LY2784544; C528327:fedratinib; D000096926:Benzenesulfonamides; C540383:ruxolitinib; C479163:tofacitinib
keywords: Aurora A kinase; Cell cycle; Cyclin D1; Fedratinib (PubChem CID: 16722836); Gandotinib (PubChem CID: 46213929); JAK inhibitors; Janus kinase; Ruxolitinib (PubChem CID: 25126798); Tofacitinib (PubChem CID: 9926791)