Klin Padiatr 2022; 234(03): 187
DOI: 10.1055/s-0042-1748735
Abstracts

Deciphering the molecular mechanism of NUP98-KDM5A chromosomal translocation in pediatric non-DS-AMKL

LN Cifarelli
1   Dep. of Pediatric Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
,
H Issa
2   Dep. of Pediatrics, Goethe-University Frankfurt, Frankfurt am Main, Germany
,
K Schuschel
2   Dep. of Pediatrics, Goethe-University Frankfurt, Frankfurt am Main, Germany
,
K Menge
1   Dep. of Pediatric Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
,
L Gack
1   Dep. of Pediatric Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
,
H J- Klusmann
2   Dep. of Pediatrics, Goethe-University Frankfurt, Frankfurt am Main, Germany
3   Authors contributed equally to the work
,
D Heckl
1   Dep. of Pediatric Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
3   Authors contributed equally to the work
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The chromosomal translocation NUP98-KDM5A (NK5A) occurs in 15% of pediatric non-Down Syndrome-Acute Megakaryoblastic Leukemia (non-DS-AMKL) and is linked to poor prognosis. To address the poorly understood molecular mechanisms of NK5A-driven leukemogenesis we overexpressed NK5A in murine fetal liver cells (mFL) Interestingly, a biphasic NK5A-mediated leukemic transformation was observed with an initial and immediate strong depletion of NK5A positive cells upon expression of the fusion oncogene. NK5A almost exclusively occurs in pediatric AMKL. Speculating on the involvement of fetal gene signatures in the NK5A-mediated transformation, we next performed a fetal signature focused CRISPR-Cas9 screening. Complementing these data with RNAseq at different time points of NK5A-mediated transformation, we were able to identify 36 high confidence candidate genes regulated by NK5A, which we will further refine with ongoing CUT&Tag Histone profiling and ATACseq. Overall, our study identified new molecular mechanisms of a biphasic NK5A-mediated leukemic transformation and will provide us new insights into potential therapeutic strategies for the treatment of high-risk pediatric AMKL.



Publication History

Article published online:
17 May 2022

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