NUP98–NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis

Wang, Gang Greg; Cai, Ling; Pasillas, Martina P.; Kamps, Mark P.

doi:10.1038/ncb1608

Cited by 401 publications

(409 citation statements)

References 35 publications

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“…23 The reasons for the discrepancy with our observations are not fully clear, but could be based on different protocols of retroviral production and transduction, or genetic differences of the mouse strains used. Interestingly, we observed in several independent experiments that expression of NUP98-NSD1 provided in vitro self-renewal capacity to Balb/C but not to C57BL/6-derived bone marrow cells.…”

Section: Discussioncontrasting

confidence: 48%

“…We also compared the expression levels of the HoxA gene cluster previously associated with transformation by NUP98-NSD1. 23 As shown in Figure 5A, we observed significant increased levels of HoxA5, HoxA7, HoxA9 and HoxA10 RNA expression in the leukemic cells; however, there was no significant difference between both experiments. In addition, there was no difference in the expression levels of the NUP98-NSD1 fusion mRNA in the leukemic blasts between both experiments.…”

Section: Resultsmentioning

confidence: 72%

“…The discrepancy between our results and those of Wang et al might also be due to a different experimental setup since we transplanted in vitro immortalized and expanded bone marrow progenitor cells following a protocol previously established for the in vivo transforming potential of MLL-fusions. 23,27,28 Nevertheless, retroviral overexpression of the NUP98-HOXA9 fusion has been previously shown also to first induce a chronic myeloproliferative disorder with progression to AML after a long latency. 29 The observed generally long latency periods for AML development in mice upon transplanting cells overexpressing different NUP98 fusions support the idea of a general indispensable acquirement of secondary mutations such as e.g.…”

Section: Discussionmentioning

confidence: 99%

“…[19][20][21][22] Previous studies have shown that retroviral overexpression of NUP98-NSD1 alone is able to induce an AML-like disease in mice after a latency of several months. 23 Here we provide experimental evidence for a potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation for the transformation of murine hematopoietic cells in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

“…15,23 In vitro transduction, proliferation and immortalization assays 1.5 × 10 5 lineage-surface marker negative (Lin-) bone marrow cells (MagCellect Kit, R&D systems, Minneapolis, USA) from 6-10 week old Balb/C or C57BL/6 mice were transduced with retrovirus on a 48-well fibronectin-coated plate according to the manufacturer's protocol (Retronectin TM , TaKaRa, Bio Inc., Shiga, Japan). The cells were selected with neomycin (0.8 mg/mL, Life Technologies, Paisley, UK) and cultured in medium containing murine stem cell factor (mSCF), FLT3 ligand, IL-11, thrombopoietin (PeproTech, Rocky Hill, NJ, USA).…”

Section: Retroviral Expression Vectorsmentioning

confidence: 99%

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

2014

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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

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Section: Discussioncontrasting

confidence: 48%

Section: Resultsmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Retroviral Expression Vectorsmentioning

confidence: 99%

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

2014

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Sotos Syndrome

Niikawa

Miyake

Matsumoto

2008

Encyclopedia of Life Sciences

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Sotos syndrome (OMIM # 117550 ) is a childhood overgrowth syndrome with distinctive craniofacial features and mental retardation. Sotos syndrome is caused by haploinsufficiency of the nuclear receptor SET domain containing protein 1 gene ( NSD1 ) located at 5q35.2‐q35.3. A wide variety of NSD1 aberrations have been found: microdeletions, intragenic deletions and missense and truncation mutations. Through in‐depth analyses of microdeletions, low copy repeat (LCR) or Alu ‐mediated rearrangements were demonstrated to be major mechanisms for de novo deletions. Therefore, Sotos syndrome is now considered as a genomic disorder. NSD1 is a protein with histone methyltransferase activity and nuclear receptor‐binding capability, both related to transcriptional controls. As pathophysiology regarding abnormalities of NSD1 protein remains unknown, further functional studies are necessary. Key concepts Haploinsufficiency of NSD1 causes Sotos syndrome. Sotos syndrome is a genomic disorder. Microdeletion involving NSD1 occurs through nonallelic homologous recombination mediated by low copy repeats or Alu elements. NSD1 has specific histone methyltransferase activity.

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