2019年11月22日 · Here, we show that two other leukemogenic proteins, nucleoporin-fusion SET-Nup214 and the NPM1 mutant, NPM1c, which contains a nuclear export signal (NES) at its C-terminus and is one of the most frequent mutations in acute myeloid leukemia, are recruited to the HOX cluster region via chromatin-bound CRM1, leading to HOX gene activation in ...

2024年12月17日 · NPM1 also contains 2 N-terminal nuclear export signal (NES) motifs that drive its nuclear export via interaction with the nuclear exporter XPO1 (CRM1) [3].

Here, we show that NPM1c directly binds to specific chromatin targets, which are co-occupied by the histone methyltransferase KMT2A (MLL1). Targeted degradation of NPM1c leads to a rapid decrease in gene expression and loss of RNA Polymerase II, as well as activating histone modifications at its targets.

2022年11月15日 · The genome-wide recruitment of NPM1c to chromatin is dependent on the nuclear exporter CRM1 and its interaction with the nuclear export signal (NES) of NPM1c. NPM1c can also be dissociated from chromatin using the CRM1 inhibitor Selinexor.

2024年10月23日 · In this study, we investigated the subcellular localization and leukemogenic potential of two rare NPM1-fusion proteins, NPM1::MLF1 and NPM1::CCDC28A. NPM1::MLF1 is present in both the...

2024年8月4日 · Chromosome Region Maintenance 1 (CRM1), also known as Exportin 1 (XPO1), is a protein that is critical for transport of proteins and RNA to the cytoplasm through the nuclear pore complex. CRM1 inhibition with small molecule inhibitors is currently being studied in many cancers, including leukemias, solid organ malignancies and brain tumors.

Nucleophosmin (NPM1) is a critical cellular protein that has been implicated in a number of pathways including mRNA transport, chromatin remodeling, apoptosis and genome stability. NPM1 function is a critical requirement for normal cellular biology ...

2023年6月26日 · Hematopoietic-specific NPM1C+ knock-in alters TAD topology leading to disrupted regulation of the cell cycle as well as aberrant chromatin accessibility and homeotic gene expression, which...

2012年8月30日 · Treatment of AML blasts with KPT-185 causes a reduction in the amount of CRM1 protein and shows a significant nuclear accumulation of CRM1 cargo proteins, such as p53 and NPM1. Using a xenograft AML mouse model, we show that in vivo treatment of leukemic mice with oral KPT-276 (analog of KPT-185 for in vivo studies) significantly prolongs ...

2016年12月1日 · Mutated nucleophosmin 1 (NPM1) acts as a proto-oncogene and is present in ~30% of patients with acute myeloid leukemia (AML). Here we examined the in vitro and in vivo anti-leukemic activity of the NPM1 and chromosome region maintenance 1 homolog (CRM1) interacting natural product avrainvillamide (A …