TY - JOUR
T1 - SH2B3 inactivation through CN-LOH 12q is uniquely associated with B-cell precursor ALL with iAMP21 or other chromosome 21 gain
AU - Sinclair, Paul B.
AU - Ryan, Sarra
AU - Bashton, Matthew
AU - Hollern, Shaun
AU - Hanna, Rebecca
AU - Case, Marian
AU - Schwalbe, Edward C.
AU - Schwab, Claire J.
AU - Cranston, Ruth E.
AU - Young, Brian D.
AU - Irving, Julie A. E.
AU - Vora, Ajay J.
AU - Moorman, Anthony Vincent
AU - Harrison, Christine J.
PY - 2019/8
Y1 - 2019/8
N2 - 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.
AB - 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.
KW - Chromosome Aberrations
KW - Chromosomes, Human, Pair 12
KW - Chromosomes, Human, Pair 21
KW - Humans
KW - Interleukin-7/pharmacology
KW - Intracellular Signaling Peptides and Proteins
KW - Loss of Heterozygosity
KW - Mutation
KW - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics
KW - Proteins/genetics
KW - STAT5 Transcription Factor/physiology
UR - http://www.scopus.com/inward/record.url?scp=85062456874&partnerID=8YFLogxK
U2 - 10.1038/s41375-019-0412-1
DO - 10.1038/s41375-019-0412-1
M3 - Article
C2 - 30816328
SN - 0887-6924
VL - 33
SP - 1881
EP - 1894
JO - Leukemia
JF - Leukemia
IS - 8
ER -