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

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 SH2B3 tumour suppressor activity in iAMP21-ALL.

Overexpression of chromatin remodeling and tyrosine kinase genes in iAMP21-positive acute lymphoblastic leukemia

“…Furthermore, we detected the known iAMP21-associated CNAs outside of chromosome 21 [7,11,15]; deletions of the tumor suppressor genes SH2B3 and RB1 were present in 40% of iAMP21 cases respectively, co-occurring in 25%. In agreement with a recent study reporting biallelic mutations and/or deletions of SH2B3 in iAMP21 [16], a majority of the SH2B3 deletions in our cohort were biallelic. Interestingly, this was also true for RB1; all deletions involving the 13q14 region were homozygous in a $80 kb region spanning RB1, and while SH2B3 RNA expression levels were unchanged in iAMP21 vs. BCP ALL without iAMP21, RB1 was significantly underexpressed in iAMP21.…”

“…Overexpression of DYRK1A could affect the balance between proliferation and differentiation in leukemic blast with iAMP21, and the quiescence promoting properties might be relevant for the relapse tendency. In a recent study on iAMP21, the authors hypothesized that DYRK1A might promote leukemia in cooperation with secondary abnormalities; however, the study did not include expression analysis to support their hypothesis [16].…”

“…The iAMP21 subtype has been investigated extensively at the genomic level, with studies describing the composition of the amplified chromosome and the mechanisms of formation [9][10][11][12][13]. Others and we have shown that iAMP21 is primary event [11] associated with specific copy number alterations (CNAs) [14][15][16], genomic fusions [7,11] and mutations in RAS pathway genes [17]. However, the only genetic alteration recurrent in all iAMP21 cases is an amplification of a 5 Mb region on chromosome 21q [11] and although the leukemia promoting mechanism in iAMP21 is thought to originate from this region, no causative genes have thus far been identified in the region.…”

Adaptor protein LNK promotes anaplastic thyroid carcinoma cell growth via 14-3-3 ε/γ binding

“…Previously, it was confirmed that LNK mutations lead to functional deficiency, which is closely related to the occurrence and development of hematological malignancies, especially in Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) and myeloproliferative neoplasms [11,[22][23][24]. Research has also shown that LNK inhibits the hematopoietic stem cell/progenitor cell response to various cytokines by inhibiting the JAK2 signaling pathway [13,22]. Furthermore, LNK can also inhibit the progression of radiation-induced acute B-cell malignant tumors in mice.…”

“…It contains a pleckstrin homology (PH) domain and a Src homology 2 (SH2) domain that specifically bind to phosphorylated tyrosine residues, which mediates signal transduction, and an N-terminal prolinerich region that mediates dimerization [8,9]. Studies have shown that LNK can inhibit wild-type or mutant JAK2 signal transduction through the SH2 domain and inhibit the activation of the JAK/STAT, ERK/MAPK, and PI3K/Akt/mTOR/GSK3β pathways [9][10][11][12][13]. Clinical studies have found that LNK mutations can lead to diabetes, heart disease, kidney injury, autoimmune hepatitis, acute lymphocytic leukemia, and bone marrow proliferative malignancies [6,[13][14][15][16][17][18].…”