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FLT3-ITD Activates RSK1 to Enhance Proliferation and Survival of AML Cells by Activating mTORC1 and eIF4B Cooperatively with PIM or PI3K and by Inhibiting Bad and BIM

1
Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
2
Department of Clinical Laboratory, Medical Hospital, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
*
Author to whom correspondence should be addressed.
Contributed equally.
Cancers 2019, 11(12), 1827; https://doi.org/10.3390/cancers11121827
Received: 25 October 2019 / Revised: 15 November 2019 / Accepted: 18 November 2019 / Published: 20 November 2019
FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously found that FLT3-ITD activates the mTORC1/S6K/4EBP1 pathway cooperatively through the STAT5/PIM and PI3K/AKT pathways to promote proliferation and survival by enhancing the eIF4F complex formation required for cap-dependent translation. Here, we show that, in contrast to BCR/ABL causing Ph-positive leukemias, FLT3-ITD distinctively activates the serine/threonine kinases RSK1/2 through activation of the MEK/ERK pathway and PDK1 to transduce signals required for FLT3-ITD-dependent, but not BCR/ABL-dependent, proliferation and survival of various cells, including MV4-11. Activation of the MEK/ERK pathway by FLT3-ITD and its negative feedback regulation by RSK were mediated by Gab2/SHP2 interaction. RSK1 phosphorylated S6RP on S235/S236, TSC2 on S1798, and eIF4B on S422 and, in cooperation with PIM, on S406, thus activating the mTORC1/S6K/4EBP1 pathway and eIF4B cooperatively with PIM. RSK1 also phosphorylated Bad on S75 and downregulated BIM-EL in cooperation with ERK. Furthermore, inhibition of RSK1 increased sensitivities to BH3 mimetics inhibiting Mcl-1 or Bcl-2 and induced activation of Bax, leading to apoptosis, as well as inhibition of proliferation synergistically with inhibition of PIM or PI3K. Thus, RSK1 represents a promising target, particularly in combination with PIM or PI3K, as well as anti-apoptotic Bcl-2 family members, for novel therapeutic strategies against therapy-resistant FLT3-ITD-positive AML. View Full-Text
Keywords: RSK; FLT3-ITD; acute myeloid leukemia; PIM; mTOR; eIF4B; BIM; Bad RSK; FLT3-ITD; acute myeloid leukemia; PIM; mTOR; eIF4B; BIM; Bad
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MDPI and ACS Style

Watanabe, D.; Nogami, A.; Okada, K.; Akiyama, H.; Umezawa, Y.; Miura, O. FLT3-ITD Activates RSK1 to Enhance Proliferation and Survival of AML Cells by Activating mTORC1 and eIF4B Cooperatively with PIM or PI3K and by Inhibiting Bad and BIM. Cancers 2019, 11, 1827. https://doi.org/10.3390/cancers11121827

AMA Style

Watanabe D, Nogami A, Okada K, Akiyama H, Umezawa Y, Miura O. FLT3-ITD Activates RSK1 to Enhance Proliferation and Survival of AML Cells by Activating mTORC1 and eIF4B Cooperatively with PIM or PI3K and by Inhibiting Bad and BIM. Cancers. 2019; 11(12):1827. https://doi.org/10.3390/cancers11121827

Chicago/Turabian Style

Watanabe, Daisuke, Ayako Nogami, Keigo Okada, Hiroki Akiyama, Yoshihiro Umezawa, and Osamu Miura. 2019. "FLT3-ITD Activates RSK1 to Enhance Proliferation and Survival of AML Cells by Activating mTORC1 and eIF4B Cooperatively with PIM or PI3K and by Inhibiting Bad and BIM" Cancers 11, no. 12: 1827. https://doi.org/10.3390/cancers11121827

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