| Abstract |
Systemic anaplastic large cell lymphoma (ALCL) without anaplastic lymphoma
kinase (ALK) positivity, was recognized as a distinct disease entity in the World
Health Organization's lymphoma classification in 2016 (ALK-ALCL).
Multiple studies have shown its similarities and differences from systemic
ALK positive ALCL, as well as from peripheral T cell lymphoma not otherwise specified
(PTCL-NOS), at epidemiological, pathogenetic and therapeutic level. In contrast
to ALK + ALCL, the prognosis of ALK-ALCL is overall worse with existing therapeutic
regimens, characterized by short periods of remission and disease control, typically
followed by relapses with extremely poor prognosis. Therefore, discovering new
treatment strategies is urgently needed.
ALK-ALCL shows pathogenetic similarities to ALK + ALCL with deregulation
of T cell receptor and CD30 receptor signaling pathways, as well as aberrations
in JAK-STAT, PI3K-Akt-Sonic Hedgehog, MAPK-mTOR-AP1 and NF-kB signaling
pathways. Abnormalities of the cytoskeleton and modification of the host’s immune
response are responsible for its morphological characteristics and aggressive clinical
course. ALK-ALCL is characterized by the presence of chromosomal translocations
and abnormal karyotype, as well as the presence of chimeric proteins, point mutations
and expression of abnormal gene transcripts.
Numerous studies have highlighted the role of the p53 signaling pathway as a
key regulator of cell cycle, cell’s survival, genetic repair, senescence and death, and
revealed the dual role of the p53 gene as a tumor suppressor gene and potential oncogene
in multicellular organisms. The role of the p53 signaling pathway, in maturation,
differentiation, activation, apoptosis, and clonal T cell expansion, as well as its implication
in the immune response, autoimmunity, and lymphomatogenesis, has also been
investigated. p53 protein levels are mainly regulated by its interaction, with the E3
ligases MDM2 and MDMX, which modify p53 post-translationally, leading to its
degradation in the proteasome.
In a significant number of cases, ALCLs carry the non-mutated p53 (wt p53)
protein, but the corresponding signaling pathway is inactive. In both ALK + and
ALK-ALCL, reactivation of the p53 signaling pathway is possible, using small inhibi tors of the MDM2 molecule. Inhibition of MDM2, caused variable inhibition of cell
proliferation and apoptosis in ALCL cell lines, indicating the presence of other p53
signaling repression mechanisms.
Data indicating that MDMX protein, a negative regulator of the p53 signaling
pathway, is involved in inactivating p53 signaling in ALCL are presented in this dissertation.
Western blot analysis showed that MDMX protein is overexpressed in ALK
+ ALCL cell lines and shows varied expression in ALK-ALCL cell lines. Immunohistochemical
analysis for MDMX protein in biopsy material from patients with ALK
+ ALCL and ALK-ALCL showed increased expression of MDMX in 78% of patients
with ALK + ALCL and in 41% of patients with ALK-ALCL (p <0.0018 Mann Whitney
test). In situ fluorescent hybridization (FISH) analysis, showed profound amplification
of the MDMX gene in 8% (1/13) of patients with ALK-ALCL as well as low
levels of multiple copies of the MDMX gene in 15% (2/13) of patients with ALKALCL
and in 27% (3/11) of patients with ALK + ALCL.
Pharmaceutical inhibition of MDMX, as well as silencing of the MDMX gene
using siRNA, were associated with reactivation of the p53 signaling pathway, cell cycle
arrest, and apoptotic cell death in ALK + and ALK- ALCL cell lines with wtp53.
These findings provide evidence that MDMX targeting may be a new therapeutic approach
for ALCL patients with wtp53 tumors.
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