title: p90RSK2 is essential for FLT3-ITD- but dispensable for BCR-ABL-induced myeloid leukemia.
abstract: p90 ribosomal S6 kinase 2 (p90RSK2) is important in diverse cellular processes including gene expression, cell proliferation, and survival. We found that p90RSK2 is commonly activated in diverse leukemia cell lines expressing different leukemogenic tyrosine kinases, including BCR-ABL and FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD). Interestingly, in a murine BM transplantation (BMT) model, genetic deficiency of RSK2 did not affect the pathogenesis or disease progression of BCR-ABL-induced myeloproliferative neoplasm (PN). In contrast, FLT3-ITD induced a T-cell acute lymphoblastic leukemia in BMT mice receiving RSK2 knockout (KO) BM cells, phenotypically distinct from the myeloproliferative neoplasm induced by FLT3-ITD using wild-type BM cells. In consonance with these results, inhibition of RSK2 by an RSK inhibitor, fmk, did not effectively induce apoptosis in BCR-ABL-expressing murine Ba/F3 cells, human K562 cells or primary tissue samples from CML patients, whereas fmk treatment induced significant apoptotic cell death not only in FLT3-ITD-positive Ba/F3 cells, human Molm14 and Mv(4;11) leukemia cells, but also in primary tissue samples from AML patients. These results suggest that RSK2 is dispensable for BCR-ABL-induced myeloid leukemia, but may be required for pathogenesis and lineage determination in FLT3-ITD-induced hematopoietic transformation. RSK2 may thus represent an alternative therapeutic target in the treatment of FLT3-ITD-positive leukemia.
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute of Emory, Atlanta, GA, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Elf
authors.forename: Dean
authors.initials: D
authors.lastname: Blevins
authors.forename: Lingtao
authors.initials: L
authors.lastname: Jin
authors.forename: Tae-Wook
authors.initials: TW
authors.lastname: Chung
authors.forename: Ifor R
authors.initials: IR
authors.lastname: Williams
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lee
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Lin
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
authors.forename: Jack
authors.initials: J
authors.lastname: Taunton
authors.forename: Hanna J
authors.initials: HJ
authors.lastname: Khoury
authors.forename: Sumin
authors.initials: S
authors.lastname: Kang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D055786:Gene Knockout Techniques; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D007951:Leukemia, Myeloid / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D051941:fms-Like Tyrosine Kinase 3; D016044:Fusion Proteins, bcr-abl; D038744:Ribosomal Protein S6 Kinases, 90-kDa