Anaplastic lymphoma kinase (ALK)-induced malignancies: novel mechanisms of cell transformation and potential therapeutic approaches.
Among the many oncogenic variants of the anaplastic lymphoma kinase (ALK), nucleophosmin 1 (NPM)/ALK fusion protein expressed in the subset of T-cell lymphoma (ALK(+)TCL) is currently the best characterized. NPM/ALK activates several signal transduction pathways, including PI3K/AKT, MEK/ERK, mTORC1, STAT3, and STAT5b. In turn, the pathways modulate expression and function of many genes and proteins involved in the key cellular functions such as proliferation, growth, survival, metabolism, and angiogenesis. Recent data indicate that NPM/ALK also promotes immune evasion of the ALK(+)TCL by inducing through STAT3 activation the expression of immunosuppressive cytokines interleukin-10 (IL-10) and transforming growth factor-beta (TGFss) and cell surface protein CD274 (PD-L1, B7-H1). In addition, NPM/ALK protects its own expression by mediating via STAT3 and at least one member of the DNA methyltransferase family DNMT1 epigenetic silencing of the SHP-1 and STAT5a genes. In ALK+TCL cells, SHP-1 and STAT5a proteins act as potent tumor suppressors by promoting degradation of the NPM/ALK protein and inhibiting expression of the NPM/ALK gene, respectively. These findings provide further rationale to therapeutically target ALK and its effector proteins, foremost STAT3. They also suggest that immunotherapeutic approaches to ALK(+)TCL and, possibly, other ALK-driven malignancies may require inhibition of ALK and STAT3 to achieve the optimal clinical efficacy.
Wasik
Mariusz A
MA
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. wasik@mail.med.upenn.edu
Zhang
Qian
Q
Marzec
Michal
M
Kasprzycka
Monika
M
Wang
Hong Yi
HY
Liu
Xiaobin
X
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D006801:Humans; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology*; D051379:Mice; D000090243:Nucleophosmin; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
C000715570:Npm1 protein, mouse; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; D000090243:Nucleophosmin; C107023:p80(NPM-ALK) protein; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases