SH2B3 inactivation through CN-LOH 12q is uniquely associated with B-cell precursor ALL with iAMP21 or other chromosome 21 gain.

Leukemia
Paul B SinclairChristine J Harrison

Abstract

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 S...Continue Reading

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Citations

Jan 16, 2020·Cancer Cell International·Zhao-Ming ZhongChuan-Zheng Sun
Feb 6, 2020·Leukemia & Lymphoma·Panagiotis Ntziachristos
May 7, 2020·Blood Cancer Journal·Kristina B Lundin-StrömBertil Johansson
Sep 3, 2020·Proceedings of the National Academy of Sciences of the United States of America·Luther DavisNancy Maizels
Mar 30, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Anouchka P LaurentSebastien Malinge
May 6, 2021·Journal of Clinical Medicine·Hiroto Inaba, Ching-Hon Pui

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Methods Mentioned

BETA
xenografts
PCR
Illumina sequencing

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