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Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
Published on: February 21, 2018
NUP98 dysregulation in myeloid leukemogenesis
M A S Moore1, K Y Chung, M Plasilova
1Moore Laboratory, Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. m-moore@ski.mskcc.org
Annals of the New York Academy of Sciences
|April 20, 2007
Summary
The NUP98-HOXA9 fusion protein drives leukemia by disrupting normal cell development and promoting uncontrolled proliferation of hematopoietic stem cells. This fusion protein alters gene expression and evades degradation, contributing to disease progression and poor prognosis in myeloid malignancies.
Area of Science:
- Hematology
- Molecular Biology
- Cancer Genetics
Background:
- Nucleoporin 98 (NUP98) is crucial for mRNA export, and its fusion with homeobox genes, such as HOXA9, results from leukemia-associated chromosomal translocations.
- The NUP98-HOXA9 fusion, linked to t(7;11)(p15;p15), is implicated in acute myeloid leukemia (AML), myelodysplastic syndrome, and chronic myeloid leukemia.
- NUP98's role in the nuclear pore complex is altered in these fusion proteins.
Purpose of the Study:
- To investigate the role of the NUP98-HOXA9 fusion gene in the development of myeloid malignancies.
- To understand the molecular mechanisms by which NUP98-HOXA9 confers a proliferative advantage and affects hematopoietic stem cell differentiation.
- To analyze the clinical significance of NUP98 alterations in AML and myelodysplastic syndrome.
Main Methods:
- Expression of NUP98-HOXA9 in murine bone marrow and human CD34(+) cells.
- Assessment of hematopoietic stem cell proliferation, differentiation, and gene expression changes.
- Analysis of NUP98 protein stability, localization, and allelic expression in patient samples.
Main Results:
- NUP98-HOXA9 expression induced myeloproliferative disease in mice, progressing to AML.
- Transduced human hematopoietic stem cells showed increased proliferation and stem cell numbers, with inhibited erythroid/myeloid differentiation.
- NUP98-HOXA9 upregulated HOXA/B, MEIS1, and Pim-1, while downmodulating globin genes and C/EBPalpha; the fusion protein was protected from degradation.
- NUP98 formed intranuclear aggregates instead of localizing to the nuclear pore complex in leukemia cells.
- Loss of heterozygosity in NUP98 was observed in 29% of AML and 8% of myelodysplastic syndrome cases, correlating with poor prognosis.
Conclusions:
- The NUP98-HOXA9 fusion protein is a potent oncogenic driver in myeloid leukemia, promoting stem cell expansion and blocking differentiation.
- Altered NUP98 localization and enhanced stability of the fusion protein contribute to leukemogenesis.
- NUP98 allelic loss is a significant adverse prognostic factor in AML and myelodysplastic syndrome.
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