NUP98/JARID1A is a novel recurrent abnormality in pediatric acute megakaryoblastic leukemia with a distinct HOX gene expression pattern

Abstract

Cytogenetic abnormalities and early response to treatment are the main prognostic factors in acute myeloid leukemia (AML). Recently, NUP98/NSD1 (t(5; 11)(q35; p15)), a cytogenetically cryptic fusion, was described as recurrent event in AML, characterized by dismal prognosis and HOXA/B gene overexpression. Using split-signal fluorescence in situ hybridization, other NUP98-rearranged pediatric AML cases were identified, including several acute megakaryoblastic leukemia (AMKL) cases with a cytogenetically cryptic fusion of NUP98 to JARID1A (t(11;15)(p15;q35)). In this study we screened 105 pediatric AMKL cases to analyze the frequency of NUP98/JARID1A and other recurrent genetic abnormalities. NUP98/JARID1A was identified in 11/105 patients (10.5%). Other abnormalities consisted of RBM15/MKL1 (n=16), CBFA2T3/GLIS2 (n=13) and MLL-rearrangements (n=13). Comparing NUP98/JARID1A-positive patients with other pediatric AMKL patients, no significant differences in sex, age and white blood cell count were found. NUP98/JARID1A was not an independent prognostic factor for 5-year overall (probability of overall survival (pOS)) or event-free survival (probability of event-free survival (pEFS)), although the 5-year pOS for the entire AMKL cohort was poor (42 ± 6%). Cases with RBM15/MLK1 fared significantly better in terms of pOS and pEFS, although this was not independent from other risk factors in multivariate analysis. NUP98/JARID1A cases were characterized by HOXA/B gene overexpression, which is a potential druggable pathway. In conclusion, NUP98/JARID1A is a novel recurrent genetic abnormality in pediatric AMKL.

Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study

“…27 Furthermore, extensive genetic characterization revealed various type II abnormalities in pediatric patients with AMKL, such as NUP98-JARID1A and MLL-PTD in addition to OTT-MAL, CBFA2T3-GLIS2, and MLL rearrangements. 28,29 In our retrospective study, additional samples were not available for such investigations, especially for abnormalities that are cytogenetically cryptic or subtle. Further genomic analysis of AMKL leukemia blasts with both normal and abnormal karyotype will improve our understanding of pathogenesis and help develop targeted therapies.…”

“…In addition, high frequencies of trisomies 21, 19, and 8 without prognostic significance in our patients are comparable with findings from other studies. 1,3,28 The biology of acquired 121 is different from that of DS-associated AMKL, which is associated with significantly better outcomes; GATA1 mutations; and frequent mutations in the cohesin complex, EZH2 and other epigenetic regulators, and JAK family kinases. 37,38 Because AMKL is frequently associated with myelofibrosis and seen in young children, it is often difficult to obtain sufficient material for cytogenetic analysis.…”

The histone demethylase Jarid1b is required for hematopoietic stem cell self-renewal in mice

“…Transcriptional regulation of HSC potential has been highly characterized, whereas more recently, epigenetic regulatory mechanisms, including DNA methylation and histone modifications, have been shown to be important in the maintenance and regulation HSC potential. [1][2][3][4] Histone demethylases, including Lsd1 5 and Jarid1a, 6 have been reported to be involved in the regulation of HSC and leukemic potential. Jarid1b (Kdm5b/Plu-1) is an H3K4me2/3 demethylase 7,8 that regulates self-renewal and differentiation in a cell type-specific manner.…”

Epigenetic regulators and their impact on therapy in acute myeloid leukemia

“…10% of AML patients with AML M7 harbor JARID1-NUP98 fusions, and expression of this fusion gene is associated with an aggressive course of disease and an adverse outcome. 102,103 Histone acetyltransferases (HAT) Histone acetyltransferases alter chromatin compaction in favor of a less compact chromatin by acetylation of lysine residues. Alterations of enzymes belonging to this group e.g.…”