INACTIVATION OF SH2B3 THROUGH CN-LOH 12Q IS UNIQUELY ASSOCIATED WITH B-CELL PRECURSOR ALL WITH IAMP21 OR OTHER CHROMOSOME 21 GAIN.
Author(s): ,
Paul Sinclair
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle Upon Tyne,United Kingdom
,
Sarra Ryan
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle Upon Tyne,United Kingdom
,
Matthew Bashton
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle Upon Tyne,United Kingdom
,
Shaun Hollern
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle Upon Tyne,United Kingdom
,
Rebecca Hanna
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle Upon Tyne,United Kingdom
,
Marian Case
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle Upon Tyne,United Kingdom
,
Edward Schwalbe
Affiliations:
Faculty of Health and Life Sciences,Northumbria University,Newcastle Upon Tyne,United Kingdom
,
Claire Schwab
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle Upon Tyne,United Kingdom
,
Ruth Cranston
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle Upon Tyne,United Kingdom
,
Zoe Hawking
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle Upon Tyne,United Kingdom
,
Brian Young
Affiliations:
Barts Cancer Institute,Queen Mary University of London,London,United Kingdom
,
Julie Irving
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle Upon Tyne,United Kingdom
,
Ajay Vora
Affiliations:
Haematology,Great Ormond Street Hospital,London,United Kingdom
,
Anthony Moorman
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle Upon Tyne,United Kingdom
Christine Harrison
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle Upon Tyne,United Kingdom
EHA Library. Sinclair P. Jun 15, 2019; 267222; PS921
Paul Sinclair
Paul Sinclair
Contributions
Abstract

Abstract: PS921

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background
In more than 30% of childhood B-cell precursor acute lymphoblastic leukaemia (B-ALL), chromosome 21 sequence is overrepresented through constitutional or acquired aneuploidy or structural rearrangements, exemplified by intrachromosomal amplification of chromosome 21 (iAMP21). How these abnormalities promote B-ALL remains obscure but a mechanistic link is suggested by the existence of shared co-occurring abnormalities.

Aims
We aimed to identify and characterise acquired genetic abnormalities that cooperate with amplification or aneuploidy of chromosome 21 to promote B-ALL.

Methods
Regions of copy neutral loss of heterozygosity and deletion were defined by analysis of SNP6.0 arrays, methylation arrays were used to assess loss of imprinting. The mutational status of SH2B3 was determined by amplicon sequencing and a homology model based on the resolved structure of the Sh2 domain of Sh2b1 was used to assess the impact of an acquired in-frame substitution. STAT activation status was determined by flow cytometric immunophenotyping.

Results
Analysis of B-ALL patients with iAMP21, other structural amplifications of chromosome 21 or constitutional or acquired additional whole copies of chromosome 21 (n=99), revealed recurrent CN-LOH of 6p, 9p and 12q. In patients without overrepresentation of chromosome 21, CN-LOH 6p and 9p were also recurrent but intriguingly, CN-LOH 12q was absent, among our own (n=203) or published cases (n=974). Further analysis demonstrated CN-LOH 12q was not associated with loss of imprinting but with homozygous mutations or deletions of the adaptor protein, SH2B3. 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. Taking into account our own cohort, analysis of archival array data and review of published cases, we conclude that in B-ALL, SH2B3 abnormalities are invariably bi-allelic, frequent in iAMP21-ALL, recurrent but less common in association with acquired aneuploidy 21 but extremely rare in the absence of overrepresentation of chromosome 21. Importantly, as iAMP21 patients are now uniformly treated as high risk, preliminary analysis of 26 patients treated on UKALL97/99 (n=5) or UKALL2003 (n=21), linked 12q abnormalities to poor outcome in iAMP21-ALL (p=0.03). Homology modelling of an iAMP21-ALL associated R392W mutation in the SH2 domain of SH2B3 demonstrated loss of critical interactions required for binding and suppression of activated JAK. Further implicating the JAK/STAT pathway as one target for SH2B3 tumour suppressor activity, stimulation with IL7 of iAMP21-ALL patient derived xenograft cells, with but not without SH2B3 inactivation, resulted in activation of STAT5 though not other STATs.

Conclusion
 

Although chromosome 21 copy number profiles are highly heterogeneous in iAMP21-ALL a limited number of candidate oncogenes are consistently amplified, overexpressed and spared from disruption by structural rearrangements.  From our data we infer that in iAMP21-ALL, high expression of one or more of these candidate genes creates strong pressure for loss of SH2B3 function while lower but still elevated expression of the same gene/s, resulting from gain of one or two copies of whole chromosome 21, produces a similar though weaker selective environment.  Since JAK/STAT activation is common in B-ALL without gain of chromosome 21 and given the near-exclusive association we observed, we are currently exploring the possibility that SH2B3 also interacts with other pathways specifically activated by increased doses of chromosome 21 genes.

Session topic: 1. Acute lymphoblastic leukemia - Biology & Translational Research

Keyword(s): B cell acute lymphoblastic leukemia, Mutation analysis, Outcome

By continuing to browse or by clicking “Accept Terms & all Cookies”, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies