Coordinated regulation of the immunoproteasome subunits by PML/RARα and PU.1 in acute promyelocytic leukemia

Abstract

Recognition and elimination of malignant cells by cytotoxic T lymphocytes depends on antigenic peptides generated by proteasomes. It has been established that impairment of the immunoproteasome subunits, that is, PSMB8, PSMB9 and PSMB10 (PSMBs), is critical for malignant cells to escape immune recognition. We report here the regulatory mechanism of the repression of PU.1-dependent activation of PSMBs by PML/RARα in the pathogenesis of acute promyelocytic leukemia (APL) and the unidentified function of all-trans retinoic acid (ATRA) as an immunomodulator in the treatment of APL. Chromatin immunoprecipitation and luciferase reporter assays showed that PU.1 directly bound to and coordinately transactivated the promoters of PSMBs, indicating that PSMBs were transcriptional targets of PU.1 and PU.1 regulated their basal expression. Analysis of expression profiling data from a large population of acute myeloid leukemia (AML) patients revealed that the expression levels of PSMBs were significantly lower in APL patients than in non-APL AML patients. Further evidence demonstrated that the decrease in their expression was achieved through PML/RARα-mediated repression of both PU.1-dependent transactivation and PU.1 expression. Moreover, ATRA but not arsenic trioxide induced the expression of PSMBs in APL cells, indicating that ATRA treatment might activate the antigen-processing/presentation machinery. Finally, the above observations were confirmed in primary APL samples. Collectively, our data demonstrate that PML/RARα suppresses PU.1-dependent activation of the immunosubunits, which may facilitate the escape of APL cells from immune surveillance in leukemia development, and ATRA treatment is able to reactivate their expression, which would promote more efficient T-cell-mediated recognition in the treatment.

Chromothripsis is linked to TP53 alteration, cell cycle impairment, and dismal outcome in acute myeloid leukemia with complex karyotype

“…Comparing chromothripsis-positive (n=13) and -negative (n=14) CK-AML, GEP disclosed a distinct gene signature of 421 significantly differentially expressed genes at a nominal Pvalue <0.05 (the top 200 differentially expressed genes are listed in Online Supplementary Table S1). Among the top most deregulated genes in chromothripsis-positive CK-AML were CCNA1 (-2.9 log fold change, P<0.009; see Online Supplementary Table S1) involved in cell cycle control and proliferation 9 and reflecting our observation of lower bone marrow blast counts in chromothripsis-positive CK-AML, PSMB10 (-1.7 log fold change, P<0.001), known to be critical for immune surveillance, 10 and PIM1 (1.9 log fold change, P<0.002; see Online Supplementary Table S1), encoding a serine threonine kinase involved in FLT3-mediated cell survival, 11 respectively ( Figure 1D). …”

PML‐RARα interferes with erythropoiesis by repressing LMO2 in acute promyelocytic leukaemia

“…In our study, we observed different changes in LMO2 expression upon ATRA or ATO treatment in NB4 cells (Figure A and B). A similar observation has been found in our previous findings, in which PSMB8 , PSMB9 and PSMB10 show response to ATRA but not ATO . LMO2 expression showed no change or even further down‐regulation in ATRA‐treated NB4 cells (Figure B).…”

Predicting RTS,S Vaccine-Mediated Protection from Transcriptomes in a Malaria-Challenge Clinical Trial

“…Although Module 1.2 or Cluster-B (in our study) did not include probe sets representing those immunoproteasome genes, the immunoproteasome is regulated by IFN-γ (70–72), and therefore, the identification of those genes may have reflected differences in IFN-γ signaling between PR and NP subjects. Furthermore, one Cluster-B gene, PML , has been identified as a regulator of the immunoproteasome (73). Also, the IFN-driven N-PLS-DA confirmed that genes related to the immunoproteasome [i.e., TAP1 (74) and PSMB8 ( LMP7 ) (70)] can be incorporated into the predictive models.…”