SH2B3 inactivation through CN-LOH 12q is uniquely associated with B-cell precursor ALL with iAMP21 or other chromosome 21 gain
Nature Publishing Group UK, 2019
academicJournal
Zugriff:
In more than 30% of B-cell precursor acute lymphoblastic leukaemia (B-ALL), chromosome 21 sequence is overrepresented through aneuploidy or structural rearrangements, exemplified by intrachromosomal amplification of chromosome 21 (iAMP21). Although frequent, the mechanisms by which these abnormalities promote B-ALL remain obscure. Intriguingly, we found copy number neutral loss of heterozygosity (CN-LOH) of 12q was recurrent in iAMP21-ALL, but never observed in B-ALL without some form of chromosome 21 gain. As a consequence of CN-LOH 12q, mutations or deletions of the adaptor protein, SH2B3, were converted to homozygosity. In patients without CN-LOH 12q, bi-allelic abnormalities of SH2B3 occurred, but only in iAMP21-ALL, giving an overall incidence of 18% in this sub-type. Review of published data confirmed a tight association between overrepresentation of chromosome 21 and both CN-LOH 12q and SH2B3 abnormalities in B-ALL. Despite relatively small patient numbers, preliminary analysis linked 12q abnormalities to poor outcome in iAMP21-ALL (p = 0.03). Homology modelling of a leukaemia-associated SH2 domain mutation and in vitro analysis of patient-derived xenograft cells implicated the JAK/STAT pathway as one likely target for SH2B3 tumour suppressor activity in iAMP21-ALL.
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SH2B3 inactivation through CN-LOH 12q is uniquely associated with B-cell precursor ALL with iAMP21 or other chromosome 21 gain
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Autor/in / Beteiligte Person: | Sinclair, Paul B. ; Ryan, Sarra ; Bashton, Matthew ; Hollern, Shaun ; Hanna, Rebecca ; Case, Marian ; Schwalbe, Edward C. ; Schwab, Claire J. ; Cranston, Ruth E. ; Young, Brian D. ; Irving, Julie A. E. ; Vora, Ajay J. ; Moorman, Anthony V. ; Harrison, Christine J. |
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Veröffentlichung: | Nature Publishing Group UK, 2019 |
Medientyp: | academicJournal |
DOI: | 10.1038/s41375-019-0412-1 |
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