THE ABUNDANCE OF CYTOTOXIC CELLS IN THE BONE MARROW TUMOR MICROENVIRONMENT OF ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS IS ASSOCIATED WITH SPECIFIC CLINICAL AND TRANSCRIPTOMIC FEATURES.

ABBATE MARÍA MERCEDES; GUERON, GERALDINE; RICCHERI, CECILIA; COTIGNOLA, JAVIER; AVENDAÑO, DANIEL; VAZQUEZ, ELBA; RUIZ, MARÍA SOL

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencias; 2022

SAIC - SAFIS - SAI

Acutelymphoblastic leukemia (ALL) is characterized by bone marrow immature lymphoidblasts overproduction and is the most incident pediatric cancer worldwide.Although overall survival and treatment efficacy has increased in recentdecades, some patients develop treatment-related acute toxicity and about15-30% of patients relapse. Whether the components of the tumormicroenvironment (TME) can contribute to the clinical heterogeneity observed inpatients is yet to be deciphered. In this work, we aimed at characterizing theimmune components of the TME in ALL by gene expression analysis and assess itsprognostic value. RNA-seq was performed in bone marrow aspirates fromArgentinian pediatric ALL patients at diagnosis (N=32). MIXTURE deconvolution method was used to estimate the proportion ofimmune cells. CD4+ T cells proportions were increased in patientsthat died or relapsed (p-val=5.6E-4). Next, we calculated a ?cytolytic score?(CS) based on the expression of 5 specific genes for cytotoxic T lymphocytesand Natural Killer cells by RNA-seq and performed validation by RT-qPCR.  Results showed that B cell proportionscorrelated with blasts percentage at diagnosis by blood smear (Spearmanrho=0.628, p-val<0.0005). We developed a custom-made method to measure theCS by RT-qPCR; results were expressed relative to healthy donor-derivedactivated peripheral blood mononuclear cells. NRF1 was selected as the reference gene (NormFinder). The CS values by RT-qPCR and RNA-seq were highlycorrelated (Spearman rho=0.817, p-val=1.56E-6) and showed >95% agreement(Bland-Altman analysis). CX3CR1(adj.p-val<0.05) and HAVCR2 (TIM-3, adj.p-val=0.067) RNA levels wereincreased in patients with high vs low CS. Overall, the TME immune component ofALL patients showcased high heterogeneity. Further, transcriptional featuressuggest an inflammatory and exhausted phenotype in the TME with high CSpatients.