CHARACTERIZING THE ETIOLOGY OF PEDIATRIC ACUTE MYELOID LEUKEMIA BY STUDYING MUTATION ACCUMULATION IN NORMAL HEMATOPOIESIS
Author(s): ,
Arianne Brandsma
Affiliations:
Princess Maxima Center for pediatric oncology,Utrecht,Netherlands
,
Rurika Oka
Affiliations:
Princess Maxima Center for pediatric oncology,Utrecht,Netherlands
,
Mark Verheul
Affiliations:
Princess Maxima Center for pediatric oncology,Utrecht,Netherlands
Ruben van Boxtel
Affiliations:
Princess Maxima Center for pediatric oncology,Utrecht,Netherlands
EHA Library. Brandsma A. Jun 15, 2019; 266846; PS1229
Arianne Brandsma
Arianne Brandsma
Contributions
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Abstract

Abstract: PS1229

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background
The incidence of leukemia peaks early in life and decreases before rising again later in life. Considering that recurrent somatic DNA mutations are thought to be the driving force behind the genesis of leukemia, this phenomenon represents an apparent paradox as young cells have less somatic (oncogenic) mutations than adult cells. Although therapy and outcome have significantly improved over the last decades, pediatric acute myeloid leukemia (pAML) remains a cancer with a high relapse rate and poor prognosis. Approximately 60% of pAML has somatic chromosomal abnormalities like translocations and inversions, while the rest is cytogenetically normal (CN). The most common chromosomal translocation 8;21 (~11% of pAML) fuses the AML1 gene on chromosome 21 to the ETO gene on chromosome 8, leading to the driver event of this pAML. In CN pAML, often single-gene mutations can be found in driver genes like FLT3, WT1 and NPM1. The various chromosomal abnormalities and mutations in combination with the different ages of onset underscore the large genetic heterogeneity of pAML. However, all these pAML subtypes receive the same treatment regimen.

Aims
To develop more targeted therapies aimed at improving survival, increased understanding of the etiology and genetic landscape of pAML is needed. We hypothesize that the underlying etiology of these different pAML subtypes differ in cellular origin and time of onset during development.

Methods
To test this hypothesis, we characterized the somatic mutations in the genomes of pAML and matched normal hematopoietic stem and progenitor cells (HSPCs) of pediatric patients with either a CN- or an AML1-ETO-driven subtype. With this knowledge, we can identify and study the mutational processes underlying the genesis of pAML as well as track down the cellular origin of the disease using a phylogenetic approach. To identify somatic mutations in the normal HSPCs, we clonally expanded primary single cells from the bone marrow biopsies to obtain sufficient DNA for whole genome sequencing (WGS) analysis.

Results
Previously, we have performed similar analyses in bone marrow- and umbilical cord blood-derived HSPCs of healthy donors and created a healthy reference line for lifelong mutation accumulation. We found that the mutation rate is higher in the pAMLs compared to the healthy HSPCs of the same patient as well as our reference line. In addition, we performed WGS on 10 HSPC clones of one pAML patient to track down its clonal origin. For this, we genotyped the observed leukemic blast somatic mutations in healthy HSPCs of the same patient and determined the genetic relatedness between these cells and the blasts. Using this approach, we constructed a developmental lineage tree and tracked down the branch that gave rise to the pAML.

Conclusion
This research provides novel insights into the etiology of pAML and differences therein between subtypes, which may contribute to the development of more targeted treatment.

Session topic: 23. Hematopoiesis, stem cells and microenvironment

Keyword(s): AML, Hematopoietic stem and progenitor cells, Pediatric, Somatic mutation

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