General AML|DNMT3A|IDH1/2|FLT3|Chromatin Regulation|Spliceosome|Cohesin|TET2

AACR 2017: Poster 2450/7 – Mutational spectrum of MLL-PTD AML patients

On Sunday 3rd April 2017, at the 107th American Association for Cancer Research (AACR) annual meeting in Washington, DC, USA, there was a poster session focused on the “Genomic Landscape of Lymphoma, Leukemia, and Lung, Bladder, and Other Cancers”.

During this session, Lingwen Ding, from the National University of Singapore, and colleagues presented results from their study.

In this study, the authors performed a whole-exome and targeted sequencing on eighty-five Partial Tandem Duplication of Mixed-lineage Leukemia Gene (MLL-PTD) Acute Myeloid Leukemia (AML) patients.

The key results were: 
  • Oncogenic driver mutations were identified in 90% of MLL-PTD patients
  • DNMT3A (25%), IDH1/2 (31%), TET1 (5%), and TET2 (16.3%) were the most frequent mutations associated with MLL-PTD
  • 67.5% of MLL-PTD patients had extensive mutations in proliferation-related pathways, most notably FLT3 mutations
  • MLL-PTD patients (26%) had more frequent cohesin pathway mutations compared to AML samples from The Cancer Genome Atlas (TCGA) (13%, P = 0.01) or meta-analysis of 1,000 AMLs (9.1%, P = 0.001)
  • A high proportion of the mutations in MLL-PTD patients had a strong tendency to disrupt the coding sequence in STAG2 compared to AML samples from TCGA; 16% vs 3%, P = 0.01
  • MLL-PTD AML patients had alterations in the RNA processing pathway including mutations in U2AF1
  • Sequential multiple mutations co-occur with MLL-PTD; IDH2/DNMT3A/U2AF1/TET2MLL-PTD→RAS-receptor tyrosine kinase

The authors concluded by stating that “MLL-PTD is acquired after those remission-persisting, initiating mutations (IDH2, DNMT3A, TET2 and U2AF1), but prior to lesions of the proliferation-related drivers”.

References
  1. Ding L. et al. Alterations in phosphatidylinositol 3-phosphate (PI3P) pathway and cAMP pathway confirm poor prognosis and reduced overall survival (OS) in a series of 209 acute myeloid leukemia patients [Poster]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2017 Apr 1–5; Washington, DC. Philadelphia (PA): AACR; 2017. Poster nr [2450/7].