Cell Proliferation Induced by the NPM-ALK Fusion Tyrosine Kinase of Anaplastic Large Cell Lymphoma Is Mediated by mTOR/S6K1 and MEK/ERK Signaling.

Abstract

The nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion is the product of the t(2;5)(p23;q35) chromosomal translocation found in approximately half of anaplastic large cell lymphomas (ALCL). Moreover, this fusion kinase, as well as other ALK fusion proteins, have been found in large B-cell lymphomas. This fusion kinase has been shown to regulate multiple signal transduction pathways and to induce hematopoietic malignancy in murine models. Nonetheless, the functional role of signaling events caused by NPM-ALK expression is incompletely understood. Here we report that NPM-ALK activates the kinase S6K1 (p70/p85) and the extracellular regulated kinase (ERK1/2). In Ba/F3 murine hematopoietic cells that express NPM-ALK, S6K1 activition by NPM-ALK was sensitive to mTOR inhibition by rapamycin. However, treatment of NPM-ALK-Ba/F3 cells with the MEK inhibitor UO126 did not attenuate the activation of S6K1 by NPM-ALK. Pharmacological inhibition of either mTOR or MEK in Ba/F3 cells expressing NPM-ALK resulted in impaired cytokine-independent outgrowth of these cells. For either inhibitor, suppression of cytokine-independent outgrowth was due to impairment of cell proliferation. In contrast, cell survival signaling was not compromised by either inhibitor alone or in combination. Combined inhibition of both the mTOR/S6K1 and MEK/ERK signaling modules resulted in an additive impairment of cytokine-independent outgrowth. Moreover, rapamycin attenuated the proliferation of the human NPM-ALK-expressing ALCL cell line Karpas299. The mTOR/S6K1 and MEK/ERK signaling modules may serve as effective chemotherapeutic targets in the treatment of ALCL and other malignancies that express the activated ALK protein tyrosine kinase.

Nuclear NPM-ALK Protects Myc from Proteasomal Degradation and Contributes to Its High Expression in Cancer Stem-Like Cells in ALK-Positive Anaplastic Large Cell Lymphoma

“…The truncated N-portion of NPM1 is responsible for the homodimerization of the fusion proteins, a configuration that triggers the autophosphorylation of multiple residues on NPM-ALK and the constitutive activation of the tyrosine kinase embodied in the truncated C-portion of ALK [ 4 ]. NPM-ALK mediates much of its oncogenic effects by binding to and activating a host of signaling proteins, thereby deregulating multiple cellular pathways that normally exert control over cell survival [ 5 ], proliferation [ 5 , 6 ], metabolism [ 7 , 8 ], the cytoskeleton [ 9 , 10 , 11 ], immune evasion [ 12 , 13 , 14 ], and maintenance of the genome integrity [ 15 , 16 , 17 ]. Accordingly, deregulations of these cellular pathways generate widespread oncogenic effects.…”