Potentiation of Nilotinib-mediated cell death in the context of the bone marrow microenvironment requires a promiscuous JAK inhibitor in CML.
In this study, we show that conditioned media (CM) generated from bone marrow (BM)-derived mesenchymal stromal cells lead to BCR-ABL independent STAT3 activation. Activation of STAT3 is important not only for survival of CML cells but also for its protection against Nilotinib (NI), within the BM microenvironment. Reducing the expression of both JAK2 and TYK2 or utilizing a pan-JAK inhibitor blocked CM-mediated STAT3 activation and sensitized CML cells to NI-mediated cell death. Finally, we demonstrate that in patient-derived primitive leukemic cells, co-cultured with BM stromal cells, inhibition of BCR-ABL and JAK activity was a successful strategy to potentiate their elimination.
Molecular Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
Rajesh R
RR
Nair
Joel H
JH
Tolentino
Raul F
RF
Argilagos
Ling
L
Zhang
Javier
J
Pinilla-Ibarz
Lori A
LA
Hazlehurst
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D053612:Janus Kinases; C498826:nilotinib