TY - JOUR
T1 - FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation
AU - Yoshimoto, Goichi
AU - Miyamoto, Toshihiro
AU - Jabbarzadeh-Tabrizi, Siamak
AU - Iino, Tadafumi
AU - Rocnik, Jennifer L.
AU - Kikushige, Yoshikane
AU - Mori, Yasuo
AU - Shima, Takahiro
AU - Iwasaki, Hiromi
AU - Takenaka, Katsuto
AU - Nagafuji, Koji
AU - Mizuno, Shin Ichi
AU - Niiro, Hiroaki
AU - Gilliland, Gary D.
AU - Akashi, Koichi
PY - 2009/12/3
Y1 - 2009/12/3
N2 - Myeloid cell leukemia-1 (MCL-1) is an essential survival factor for hematopoiesis. In humans, hematopoietic stem cells (HSCs) express MCL-1 at the highest level in response to FMS-like tyrosine kinase-3 (FLT3) signaling. We here show that this FLT3-dependent stem cell maintenance system also plays a critical role in survival of leukemic stem cells (LSCs) in acute myeloid leukemia (AML). The CD34+CD38- LSC fraction expresses high levels of FLT3 as well as MCL-1, even compared with normal HSCs. Treatment with FLT3 ligand induced further MCL-1 up-regulation in LSCs in all AML cases tested. Interestingly, the group of samples expressing the highest levels of MCL-1 constituted AML with FLT3-internal tandem duplications (ITD). In FLT3-ITD AML cell lines, cells expressed a high level of MCL-1, and an inhibition of MCL-1 induced their apoptotic cell death. A tyrosine kinase inhibitor suppressed MCL-1 expression, and induced apoptosis that was reversed by the enforced MCL-1 expression. Finally, transduction of FLT3-ITD into HSCs strongly activated MCL-1 expression through its signal transducer and activator of transcription 5 (STAT5)-docking domains. This effect was completely abrogated when STAT5 activation was blocked. Thus, the acquisition of FLT3-ITD ensures LSC survival by upregulating MCL-1 via constitutive STAT5 activation that is independent of wild-type FLT3 signaling.
AB - Myeloid cell leukemia-1 (MCL-1) is an essential survival factor for hematopoiesis. In humans, hematopoietic stem cells (HSCs) express MCL-1 at the highest level in response to FMS-like tyrosine kinase-3 (FLT3) signaling. We here show that this FLT3-dependent stem cell maintenance system also plays a critical role in survival of leukemic stem cells (LSCs) in acute myeloid leukemia (AML). The CD34+CD38- LSC fraction expresses high levels of FLT3 as well as MCL-1, even compared with normal HSCs. Treatment with FLT3 ligand induced further MCL-1 up-regulation in LSCs in all AML cases tested. Interestingly, the group of samples expressing the highest levels of MCL-1 constituted AML with FLT3-internal tandem duplications (ITD). In FLT3-ITD AML cell lines, cells expressed a high level of MCL-1, and an inhibition of MCL-1 induced their apoptotic cell death. A tyrosine kinase inhibitor suppressed MCL-1 expression, and induced apoptosis that was reversed by the enforced MCL-1 expression. Finally, transduction of FLT3-ITD into HSCs strongly activated MCL-1 expression through its signal transducer and activator of transcription 5 (STAT5)-docking domains. This effect was completely abrogated when STAT5 activation was blocked. Thus, the acquisition of FLT3-ITD ensures LSC survival by upregulating MCL-1 via constitutive STAT5 activation that is independent of wild-type FLT3 signaling.
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U2 - 10.1182/blood-2008-12-196055
DO - 10.1182/blood-2008-12-196055
M3 - Article
C2 - 19808698
AN - SCOPUS:73949096431
SN - 0006-4971
VL - 114
SP - 5034
EP - 5043
JO - Blood
JF - Blood
IS - 24
ER -