DNMT3A,   IDH1/2,  NPM1,  RUNX1,  Spliceosome,  Chromatin Regulation

Co-occurring mutations in pediatric FLT3-ITD leukemia

Although somatic mutation burden in acute myeloid leukemia (AML) is low compared with other tumor types, there are certain genetic and epigenetic dysregulations typical for the disease. Examples of functional classes often disrupted by mutations in AML are:  signalling and kinase pathways, nucleophosmin (NPM1) functions, transcription factors, tumor suppressors, spliceosome complexes, cohesin complexes and epigenetic modifiers (DNA methylation and chromatin modification).1 Cytogenetic information is used at diagnosis to stratify adult patients with AML into risk categories (favorable, intermediate, unfavorable)2, 3, however, pediatric AML is different to adult AML, both in terms of genomic alterations and therapeutic response.  

Daelynn R Buelow, Division of Pharmaceutics and Pharmaceutical Chemistry, Ohio State University, US, and colleagues4 conducted a study to define and understand mutations that occur alongside the common Fms-like tyrosine kinase 3 (FLT3 ) -internal tandem duplication (ITD) mutation in pediatric AML.3 They used RNA sequencing and an analysis of known AML associated gene mutations (MLL-PTD, DNMT3A, U2AF1, FLT3 -ITD, and IDH2) to identify co-occurring mutations and analyse changes in clonal heterogeneity between diagnosis and relapse (by the assessment of variant allele frequency; VAF) in a cohort of 37 cytogenetically normal FLT3-ITD–positive pediatric patients with AML.   

Results:
  • FLT3-ITD was seen in all samples at diagnosis and relapse
  • 56% of cases had chimeric transcripts including MLL-PTD, NUP98-NSD1, CBFB-MYH11, and DEK-NUP214
  • Fusions were seen between BCL11B and either RUNX1 or ZEB2, and this was associated with a >40 fold increase in BCL11B When BCL11B was overexpressed in a pediatric FLT3-ITD–positive cell line, MV4-11, cells became less sensitive to etoposide and more sensitive to clofarabine
  • Several co-occurring mutations in tumor suppressor, transcription factor, cohesin complex, methylation related, chromatin remodelling, kinases, Ras pathway, and signalling genes were described. These occurred with a VAF of 0.1 or more
  • Most common co-occurring mutations were WT1 (median VAF = 0.4) and NPM1 (median VAF = 0.41) representing 35% of mutations observed. The authors reported that the WT1 mutation was present in all of the cohorts relapsed samples, and in most cases was the same variant as seen at diagnosis
  • NUP98-NSD1 was associated with poorer outcome (event-free survival, p=0.03) whereas NPM1, WT1 and an FLT3 AR (allelic ratio) of ≥4 were not
  • In terms of clonal patterns during disease progression, analysis of samples revealed all three clonal patterns to relapse (regrowth of leukemic stem cells; LSCs), outgrowth of diagnostic LSC clones, and the outgrowth of preleukemic hematopoietic stem cells
Conclusions:
  • WT1 mutational ‘hotspot’ is around exon 7 (N-terminal zinc finger domains) and may have a role in disease progression in conjunction with FLT3-ITD in pediatric AML
  • BC11B fusion genes and BCL11B overexpression may be involved in chemo-resistance to etoposide in pediatric AML with FLT3-ITD mutation
  • The team postulate that the use of this kind of genomic level analysis of samples (diagnostic and relapse) could reveal problematic clones requiring alternative and complex treatment, thus improving treatment strategies
References
  1. DiNardo C.D. and Cortes J. E. Mutations in AML: prognostic and therapeutic implications. Hematology Am Soc Hematol Educ Program. 2016 Dec 2;2016(1):348-355. DOI: 10.1182/asheducation-2016.1.348.
  2. Tallman M. S. et al., NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Acute Myeloid Leukaemia. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf Published; August 13 2019 [Accessed September 1 2019]
  3. Döhner H. et al., Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017 Jan 26;129(4):424-47. DOI: 10.1182/blood-2016-08-733196
  4. Buelow D. R. et al., Uncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT3-ITD AML. Clin Transl Sci. 2019 Jul 26. DOI: 10.1111/cts.12669. [Epub ahead of print]
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