Lyn sustains oncogenic signaling in chronic lymphocytic leukemia by strengthening SET-mediated inhibition of PP2A

Abstract

Key Points• Cytosolic HSP90-bound Lyn mediates resistance to apoptosis by strengthening PP2A/SET interaction in CLL cells.• FTY720-analogues antagonizing the PP2A/SET interaction and Lyn inhibitors may provide a therapeutic approach of CLL.Aberrant protein kinase activities, and the consequent dramatic increase of Ser/Thr and -Tyr phosphorylation, promote the deregulation of the survival pathways in chronic lymphocytic leukemia (CLL), which is crucial to the pathogenesis and progression of the disease. In this study, we show that the tumor suppressor protein phosphatase 2A (PP2A), one of the major Ser/Thr phosphatases, is in an inhibited form because of the synergistic contribution of 2 events, the interaction with its physiologic inhibitor SET and the phosphorylation of Y307 of the catalytic subunit of PP2A. The latter event is mediated by Lyn, a Src family kinase previously found to be overexpressed, delocalized, and constitutively active in CLL cells. This Lyn/PP2A axis accounts for the persistent high level of phosphorylation of the phosphatase's targets and represents a key connection linking phosphotyrosine-and phosphoserine/threonine-mediated oncogenic signals.The data herein presented show that the disruption of the SET/PP2A complex by a novel FTY720-analog (MP07-66) devoid of immunosuppressive effects leads to the reactivation of PP2A, which in turn triggers apoptosis of CLL cells. When used in combination with SFK inhibitors, the action of MP07-66 is synergistically amplified, providing a new option in the therapeutic strategy for CLL patients. (Blood. 2015;125(24):3747-3755) IntroductionChronic lymphocytic leukemia (CLL), the most common leukemia in the Western world, is characterized by the proliferation of CD5 1 / CD19 1 /CD231 B lymphocytes in lymphoid tissues and bone marrow, which progressively accumulate as mature quiescent cells in the peripheral blood. 1,2 A key role in proliferation and survival of CLL cells is played by microenvironmental factors, which in turn trigger multiple signals mediated by cell surface receptors including CD40, toll-like receptor and B-cell receptor (BCR). [3][4][5] The efforts toward a therapeutic intervention, besides the standard chemo-immunotherapy, have recently focused on hyperactive kinases downstream of the BCR, 6,7 with the development of therapeutically promising inhibitors of these enzymes. [8][9][10] Lyn, for instance, a tyrosine kinase belonging to the Src family kinases (SFKs), has been shown to play a crucial role in the onset and progression of CLL. In CLL cells, Lyn is overexpressed and distributed into 2 pools, one associated beneath the cell surface and the other bound to an aberrant cytosolic complex, which exhibits the constitutive activation responsible for the phosphorylation of a myriad of protein targets in the cytosol and for the resistance of CLL cells to apoptosis. 11-13Because Lyn-targeting drugs, such as dasatinib, 14,15 have yielded disappointing results in managing CLL, [16][17][18][19] we have recently focused on the substrates of...

WDR5 high expression and its effect on tumorigenesis in leukemia

“…Lyn, a gene target of WDR5, is a tyrosine kinase belonging to the Src family kinases (SFKs) and plays a crucial role in the onset and progression of CLL [39–42]. It has been reported that the existence of a TK network composed of the tyrosine AXL, Lyn and SYK, promotes cell resistance to nilotinib treatment and drives Bcr–Abl-independent CML cell proliferation.…”

Targeting PP2A in cancer: Combination therapies

“…Phosphorylation of FTY720 allows it to act as a functional antagonist of the sphingosine-1-phosphate receptors (S1PRs), leading to sequestration of lymphocytes and immune suppression [29, 30]. Analogs of FTY720 that are incapable of being phosphorylated by sphingosine kinase-2 lack these immunosuppressive properties but retain their ability to activate PP2A and induce apoptosis [31-33], suggesting that the effect on PP2A is independent of S1PR related signaling.…”

“…An additional example of oncogene-induced PP2A inactivation was proposed in a model of chronic lymphocytic leukemia (CLL) [33]. The authors demonstrated increased phosphorylation of PP2A-C at Tyr307 in CLL cells but not normal B cells, and conclude that PP2A-C hyperphosphorylation is a result of LYN (a SRC family kinase) overexpression and leads to PP2A inhibition via increased association of PP2A-C with SET.…”

Biophysical Characterization and Expression Analysis of Kv1.3 Potassium Channel in Primary Human Leukemic B Cells

“…Antigen binding to the BCR induces clustering of BCR components at the cell membrane, along with phosphorylation of some components by activated Src family kinases (Lyn, Blk) e.g. [32]. We have previously shown that in T cells, tyrosine phosphorylation of Kv1.3 by the Src family kinase p56lck resulted in a decrease of its activity [33].…”