Potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation in acute myeloid leukemia induction

Abstract

The NUP98-NSD1 fusion, product of the t(5;11)(q35;p15.5) chromosomal translocation, is one of the most prevalent genetic alterations in cytogenetically normal pediatric acute myeloid leukemias and is associated with poor prognosis. Co-existence of an FLT3-ITD activating mutation has been found in more than 70% of NUP98-NSD1-positive patients. To address functional synergism, we determined the transforming potential of retrovirally expressed NUP98-NSD1 and FLT3-ITD in the mouse. Expression of NUP98-NSD1 provided mouse strain-dependent, aberrant self-renewal potential to bone marrow progenitor cells. Co-expression of FLT3-ITD increased proliferation and maintained self-renewal in vitro. Transplantation of immortalized progenitors co-expressing NUP98-NSD1 and FLT3-ITD into mice resulted in acute myeloid leukemia after a short latency. In contrast, neither NUP98-NSD1 nor FLT3-ITD single transduced cells were able to initiate leukemia. Interestingly, as reported for patients carrying NUP98-NSD1, an increased Flt3-ITD to wild-type Flt3 mRNA expression ratio with increased FLT3-signaling was associated with rapidly induced disease. In contrast, there was no difference in the expression levels of the NUP98-NSD1 fusion or its proposed targets HoxA5, HoxA7, HoxA9 or HoxA10 between animals with different latencies to develop disease. Finally, leukemic cells co-expressing NUP98-NSD1 and FLT3-ITD were very sensitive to a small molecule FLT3 inhibitor, which underlines the significance of aberrant FLT3 signaling for NUP98-NSD1-positive leukemias and suggests new therapeutic approaches that could potentially improve patient outcome. Potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation in acute myeloid leukemia induction

The Role of Nuclear Receptor–Binding SET Domain Family Histone Lysine Methyltransferases in Cancer

“…This persistent methylation prevents transcriptional repression of the Hox-A locus by EZH2 causing progenitor immortalization (Wang et al 2007). Though the NUP98-NSD1 fusion protein occurs in a low percentage of patients, the incidence of concurrence between NUP98-NSD1 and FLT3 (FMS-like tyrosine kinase 3) internal tandem duplication (ITD) mutants is high (70%) in human AML cases (Thanasopoulou et al 2014). Co-infection of progenitor cells expressing both NUP98-NSD1 and FLT3-ITD mutation resulted in a strikingly decreased latency of development of AML in mice compared to those reconstituted with NUP98-NSD1 alone (Thanasopoulou et al 2014).…”

“…Though the NUP98-NSD1 fusion protein occurs in a low percentage of patients, the incidence of concurrence between NUP98-NSD1 and FLT3 (FMS-like tyrosine kinase 3) internal tandem duplication (ITD) mutants is high (70%) in human AML cases (Thanasopoulou et al 2014). Co-infection of progenitor cells expressing both NUP98-NSD1 and FLT3-ITD mutation resulted in a strikingly decreased latency of development of AML in mice compared to those reconstituted with NUP98-NSD1 alone (Thanasopoulou et al 2014). Furthermore, experiments using immortalized bone marrow progenitor cells demonstrate that NUP98-NSD1 promotes the expression and activation of FLT3-ITD, suggesting a potent cooperation between NUP98-NSD1 and FLT3-ITD during leukemic transformation that may be therapeutically targeted with SET domain or FLT3 inhibitors (Thanasopoulou et al 2014).…”

Concealed dagger in FLT3/ITD+ AML

“…Specifically, this team is currently evaluating the feasibility, utility, and efficacy of an interactive patient education program coupled with a web-based medication scheduling and text-messaging reminder system that uses cell phones to remind parents to give the 6-MP. 6 Remember that despite the ability to identify subsets of patients with ALL at extremely high risk of relapse based on blast cell genetics and/or measures of response, 7 the majority of deaths in children and adolescents with ALL actually occur among those with good-risk clinical features, because those with a favorable prognosis represent the majority of pediatric patients with ALL. 2 It is conceivable then that many of these better-risk patients have chemotherapyresponsive disease and with adequate adherence will be cured.…”

“…FLT3/ITD may coexist with many other mutations but only few specific gene pairs including the FLT3/ITD and NUP98/NSD1 combination are powerful enough to initiate leukemia. 6 If, as suggested by Gilliland and Griffin, in all AML cells an aberrant proliferative signal is present along with impairment in differentiation process, it is interesting to decipher what makes cells harboring the FLT3/ITD and NUP98/NDS1 combination so resistant to chemotherapy. FLT3/ITD, is a strong driver for proliferation and beyond conventional cytogenetics, is the most common genetic aberration of definitive clinical significance in AML.…”

“…In vitro data suggest that FLT3 inhibitors may be an option. 6 Unfortunately, no clinical evidence favoring specific agents exist for patients presenting with both FLT3/ITD and NUP98/NSD1. In addition, because NUP98 can partner multiple other genes yielding oncogenic signals, it is worth exploring the clinical effect of other NUP98-related fusion transcripts.…”