ALPS AND ALPS-LIKE DISORDERS AND THE RISK OF MALIGNANCY
HUMAN PI3K MUTATIONS: IMMUNODEFICIENCY AND MALIGNANCY
APOPTOSIS DEFECTS DISCRIMINATE THE RAS-ASSOCIATED LYMPHOPROLIFERATIVE DISEASE (RALD) AND JUVENILE MYELOMONOCYTIC LEUKAEMIA (JMML) CONDITIONS
Abstract
Background and Aims
KRAS or NRAS somatic mutations are associated with JMML, a rare pediatric malignancy, or with RALD, a benign autoimmune leukoproliferative disease. We and others proposed that RALD and JMML could be a clinical continuum with various additional genetic events. Lymphocytes from RALD patients exhibit a resistance to the BIM-mediated Activated-Cell Autonomous Death (ACAD), but a normal FAS/FASLG-mediated Activation-Induced Cell Death (AICD). We studied these apoptosis pathways in JMML and RALD.
Methods
We performed AICD and ACAD analysis on T-cells from 4 RALD, 6 Long survivor (LS)-JMML and 6 Severe (S)-JMML. We also evaluated these apoptosis functions in a RALD patient who developed leukaemia. Lastly, we assessed the BIM and FASL expression in these conditions.
Results
Whereas RALD T cells exhibit an ACAD defect (related to a decrease of BIM), we observed a normal ACAD but a defective AICD in JMML T cells. This AICD defect is linked to a FASL downregulation along with modulation of Perforin, TRAIL, TNF and Granzyme levels. In a RALD condition which transformed into leukaemia, we observed a progressive AICD defect related to a FASL downregulation as the consequence of a monocyte-induced FASL methylation profile.
Conclusions
We unraveled a key role of JMML monocytes associated, with a modification of apoptosis genes regulation in T cells, likely protecting tumor cells from T-cell cytotoxicity. Assessing the apoptosis functions in RAS mutated patients could be a prognosis tool whereas targeting this epigenetic process could open new avenues in JMML treatments.