Aggressive NK-Cell Leukemia:Clinical Subtypes,Treatments,Prognosis And JAK/STAT-MYC-Biosynthesis Axis Activation

Aggressive NK-cell leukemia(ANKL)is a catastrophic,systemic disease with dismal prognosis.We conducted a multicenter retrospective study of 113 cases of ANKL.The median overall survival was 55 days and 1-year survival rate was 4.42%(5/113).Prior to the fulminant onset,18 patients(15.93%)manifested infectious mononucleosis-like symptoms for more than three months(median 4 months,range:3-15 months).Compared to the other ANKL cases,these patients showed female predominance(P = 0.007),more alleviated symptoms,better prognosis(P<0.001),and lower TP53 mutation rates(P = 0.038),representing a clinical subtype of ANKL.Survival analysis revealed L-asparaginase,methotrexate and dexamethasone(AspaMetDex)was an effective induction regimen with no therapy-related mortality.The complete remission rate and overall response rate in newly diagnosed patients was 30.77%(4/13)and 76.92%(10/13),respectively.Multivariate analysis showed serum LDH level,clinical subtype and administration of L-asparagine based chemotherapy or allo-HSCT were factors independently predictive for survival.These data depicted novel features of ANKL and provided insights into its treatments and outcomes.Besides the multicenter retrospective analysis,we also conducted whole genome,transcriptome and targeted sequencing,cytokine-array as well as functional assays to perform the first comprehensive study of ANKL.Mutations in the JAK-STAT pathway were identified in 48%(14/29)of ANKL patients,while the extracellular STAT3 stimulator IL-10 was elevated by an average of 56 fold(P<0.0001)in the plasma of all patients examined.Additional frequently mutated genes included TP53(34%),TET2(28%),CREBBP(21%)and MLL2(21%).Patient NK leukemia cells showed prominent activation of STAT3 phosphorylation,MYC expression and transcriptional activities in multiple metabolic pathways.Functionally,STAT3 activation and MYC expression were critical for the proliferation and survival of ANKL cells.STAT signaling regulated the MYC transcription program,and both STAT signaling and MYC transcription were required to maintain the activation of nucleotide synthesis and glycolysis.Collectively,The JAK-STAT pathway represents a major target for genomic alterations and IL-10 stimulation in ANKL.This newly discovered JAK/STAT-MYC-Biosynthesis axis may provide opportunities for the development of novel therapeutic strategies in treating this subtype of leukemia.