FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation

Goichi Yoshimoto, Toshihiro Miyamoto, Siamak Jabbarzadeh-Tabrizi, Tadafumi Iino, Jennifer L. Rocnik, Yoshikane Kikushige, Yasuo Mori, Takahiro Shima, Hiromi Iwasaki, Katsuto Takenaka, Koji Nagafuji, Shin Ichi Mizuno, Hiroaki Niiro, Gary D. Gilliland, Koichi Akashi

Research output: Contribution to journalArticlepeer-review

138 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)5034-5043
Number of pages10
JournalBlood
Volume114
Issue number24
DOIs
Publication statusPublished - Dec 3 2009

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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