HAEM5:Acute myeloid leukaemia with NUP98 rearrangement: Difference between revisions
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==Gene Rearrangements== | ==Gene Rearrangements== | ||
Acute myeloid leukemia (AML) with ''NUP98'' rearrangement is characterized by chromosomal translocations involving ''NUP98'' (nucleoporin 98 and 96 precursor) on chromosome 11p15.4 and various partner genes - more than 40 of such have been reported to date.<ref>Patkar N, Meshinchi S, Westerman D, et al. Acute myeloid leukaemia with NUP98 rearrangement. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. Lyon (France): International Agency for Research on Cancer; 2024. . (WHO classification of tumours series, 5th ed.; vol. 11). <nowiki>https://publications.iarc.who.int/637</nowiki>.</ref> The ''NUP98'' gene encodes protein component of the nuclear pore complex which facilitates nucleocytoplasmic transport of RNA and has roles in transcriptional and cell cycle regulation.<ref name=":2">{{Cite journal|last=Gough|first=Sheryl M.|last2=Slape|first2=Christopher I.|last3=Aplan|first3=Peter D.|date=2011-12-08|title=NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights|url=https://pubmed.ncbi.nlm.nih.gov/21948299|journal=Blood|volume=118|issue=24|pages=6247–6257|doi=10.1182/blood-2011-07-328880|issn=1528-0020|pmc=3236115|pmid=21948299}}</ref><ref name=":4">{{Cite journal|last=Michmerhuizen|first=Nicole L.|last2=Klco|first2=Jeffery M.|last3=Mullighan|first3=Charles G.|date=2020-11-12|title=Mechanistic insights and potential therapeutic approaches for NUP98-rearranged hematologic malignancies|url=https://pubmed.ncbi.nlm.nih.gov/32766874|journal=Blood|volume=136|issue=20|pages=2275–2289|doi=10.1182/blood.2020007093|issn=1528-0020|pmc=7702474|pmid=32766874}}</ref> NUP98 fusion proteins typically involve the N-terminal portion of NUP98 and the C-terminal portion of the fusion partner.<ref name=":3">{{Cite journal|last=Gough|first=Sheryl M.|last2=Slape|first2=Christopher I.|last3=Aplan|first3=Peter D.|date=2011-12-08|title=NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights|url=https://pubmed.ncbi.nlm.nih.gov/21948299|journal=Blood|volume=118|issue=24|pages=6247–6257|doi=10.1182/blood-2011-07-328880|issn=1528-0020|pmc=3236115|pmid=21948299}}</ref> Fusion partners commonly include transcription factors (such as ''HOX'' elements, most often ''HOXA9'') or epigenetic regulators (most commonly involving ''NSD1'' or ''KDM5A''), however a range of partners belonging to neither of these categories has been identified, many of which contain coiled-coil domains thought to facilitate oligomerization.<ref name=":0">{{Cite journal|last=Mohanty|first=Sagarajit|date=2023-09|title=NUP98 Rearrangements in AML: Molecular Mechanisms and Clinical Implications|url=https://www.mdpi.com/2673-7523/3/3/11|journal=Onco|language=en|volume=3|issue=3|pages=147–164|doi=10.3390/onco3030011|issn=2673-7523}}</ref><ref name=":3" /> | Acute myeloid leukemia (AML) with ''NUP98'' rearrangement is characterized by chromosomal translocations involving ''NUP98'' (nucleoporin 98 and 96 precursor) on chromosome 11p15.4 and various partner genes - more than 40 of such have been reported to date.<ref name=":5">Patkar N, Meshinchi S, Westerman D, et al. Acute myeloid leukaemia with NUP98 rearrangement. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. Lyon (France): International Agency for Research on Cancer; 2024. . (WHO classification of tumours series, 5th ed.; vol. 11). <nowiki>https://publications.iarc.who.int/637</nowiki>.</ref> The ''NUP98'' gene encodes protein component of the nuclear pore complex which facilitates nucleocytoplasmic transport of RNA and has roles in transcriptional and cell cycle regulation.<ref name=":2">{{Cite journal|last=Gough|first=Sheryl M.|last2=Slape|first2=Christopher I.|last3=Aplan|first3=Peter D.|date=2011-12-08|title=NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights|url=https://pubmed.ncbi.nlm.nih.gov/21948299|journal=Blood|volume=118|issue=24|pages=6247–6257|doi=10.1182/blood-2011-07-328880|issn=1528-0020|pmc=3236115|pmid=21948299}}</ref><ref name=":4">{{Cite journal|last=Michmerhuizen|first=Nicole L.|last2=Klco|first2=Jeffery M.|last3=Mullighan|first3=Charles G.|date=2020-11-12|title=Mechanistic insights and potential therapeutic approaches for NUP98-rearranged hematologic malignancies|url=https://pubmed.ncbi.nlm.nih.gov/32766874|journal=Blood|volume=136|issue=20|pages=2275–2289|doi=10.1182/blood.2020007093|issn=1528-0020|pmc=7702474|pmid=32766874}}</ref> NUP98 fusion proteins typically involve the N-terminal portion of NUP98 and the C-terminal portion of the fusion partner.<ref name=":3">{{Cite journal|last=Gough|first=Sheryl M.|last2=Slape|first2=Christopher I.|last3=Aplan|first3=Peter D.|date=2011-12-08|title=NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights|url=https://pubmed.ncbi.nlm.nih.gov/21948299|journal=Blood|volume=118|issue=24|pages=6247–6257|doi=10.1182/blood-2011-07-328880|issn=1528-0020|pmc=3236115|pmid=21948299}}</ref> Fusion partners commonly include transcription factors (such as ''HOX'' elements, most often ''HOXA9'') or epigenetic regulators (most commonly involving ''NSD1'' or ''KDM5A''), however a range of partners belonging to neither of these categories has been identified, many of which contain coiled-coil domains thought to facilitate oligomerization.<ref name=":0">{{Cite journal|last=Mohanty|first=Sagarajit|date=2023-09|title=NUP98 Rearrangements in AML: Molecular Mechanisms and Clinical Implications|url=https://www.mdpi.com/2673-7523/3/3/11|journal=Onco|language=en|volume=3|issue=3|pages=147–164|doi=10.3390/onco3030011|issn=2673-7523}}</ref><ref name=":3" /> | ||
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|'''Driver Gene''' | |'''Driver Gene''' | ||
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==Epigenomic Alterations== | ==Epigenomic Alterations== | ||
NUP98 fusion proteins are understood to generally mediate leukemogenesis through the functions of protein domains present in wild-type ''NUP98'' and the relevant fusion partner (often harbouring transcriptional or chromatin-modifying properties); ''in vitro'' experiments have demonstrated chromatin remodeling related to fusion oncoprotein expression (and associated with coordination of numerous interacting proteins, including transcriptional cofactors (e.g. EP300, CREBBP, MEIS1) and histone-modifying complexes) resulting in dysregulation of expression of members of the ''HOXA'' and ''HOXB'' gene families, among other loci (e.g. ''MEIS1'').<ref name=":4" /><ref name=":5" /> | |||
==Genes and Main Pathways Involved== | ==Genes and Main Pathways Involved== | ||