p90RSK2 is essential for FLT3-ITD- but dispensable for BCR-ABL-induced myeloid leukemia

Shannon Elf, Dean Blevins, Lingtao Jin, Tae Wook Chung, Ifor R. Williams, Benjamin H. Lee, Jian Xin Lin, Warren J. Leonard, Jack Taunton, Hanna J. Khoury, Sumin Kang

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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 BCRABL 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. RSK2maythus represent an alternative therapeutic target in the treatment of FLT3-ITD-positive leukemia.

Original languageEnglish (US)
Pages (from-to)6885-6894
Number of pages10
JournalBlood
Volume117
Issue number25
DOIs
StatePublished - Jun 23 2011
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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