NF-kappaB inhibition triggers death of imatinib-sensitive and imatinib-resistant chronic myeloid leukemia cells including T315I Bcr-Abl mutants.
The Bcr-Abl inhibitor imatinib is the current first-line therapy for all newly diagnosed chronic myeloid leukemia (CML). Nevertheless, resistance to imatinib emerges as CML progresses to an acute deadly phase implying that physiopathologically relevant cellular targets should be validated to develop alternative therapeutic strategies. The NF-kappaB transcription factor that exerts pro-survival actions is found abnormally active in numerous hematologic malignancies. In the present study, using Bcr-Abl-transfected BaF murine cells, LAMA84 human CML cell line and primary CML, we show that NF-kappaB is active downstream of Bcr-Abl. Pharmacological blockade of NF-kappaB by the IKK2 inhibitor AS602868 prevented survival of BaF cells expressing either wild-type, M351T or T315I imatinib-resistant mutant forms of Bcr-Abl both in vitro and in vivo using a mouse xenograft model. AS602868 also affected the survival of LAMA84 cells and of an imatinib-resistant variant. Importantly, the IKK2 inhibitor strongly decreased in vitro survival and ability to form hematopoietic colonies of primary imatinib resistant CML cells including T315I cells. Our data strongly support the targeting of NF-kappaB as a promising new therapeutic opportunity for the treatment of imatinib resistant CML patients in particular in the case of T315I patients. The T315I mutation escapes all currently used Bcr-Abl inhibitors and is likely to become a major clinical problem as it is associated with a poor clinical outcome.
INSERM U895/ C3M: Centre Méditerranéen de Médecine Moléculaire, Nice, France.
Nadia
N
Lounnas
Catherine
C
Frelin
Nadège
N
Gonthier
Pascal
P
Colosetti
Anne
A
Sirvent
Jil-Patrice
JP
Cassuto
Fréderic
F
Berthier
Nicolas
N
Sirvent
Philippe
P
Rousselot
Michel
M
Dreano
Jean-François
JF
Peyron
Véronique
V
Imbert
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D016313:Genes, abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001549:Benzamides; D016328:NF-kappa B; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate