SH2B3 – Acute lymphoblastic leukemia predisposition

SH2B3 has been implicated in predisposition to childhood acute lymphoblastic leukemia (ALL) through both germline and somatic events. In a cohort of 57 high hyperdiploid ALL patients, one individual harbored a heterozygous germline frameshift mutation, c.1228del (p.Gly409_Ile410insTer), predicted to truncate the adaptor protein SH2B3 and impair its inhibitory function on JAK/STAT signaling (1 proband) (PMID:31102422). Additionally, in B-cell precursor ALL with intrachromosomal amplification of chromosome 21 (iAMP21), copy-neutral loss of heterozygosity at 12q resulted in bi-allelic SH2B3 inactivation in 18% of cases, underscoring a recurrent somatic mechanism in this subtype (PMID:30816328).

Although direct functional assays in ALL models are lacking, SH2B3 is established as a negative regulator of cytokine receptor signaling. Loss-of-function via germline truncation or somatic bi-allelic inactivation supports a haploinsufficiency/tumor suppressor mechanism that likely enhances JAK/STAT pathway activity in leukemogenesis. Additional studies are needed to confirm the impact of SH2B3 disruption on leukemia initiation and progression. Key take-home: SH2B3 loss-of-function events confer a predisposition to acute lymphoblastic leukemia and represent a potential marker for risk stratification.

References

• Genes, chromosomes & cancer • 2019 • Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children. PMID:31102422
• Leukemia • 2019 • SH2B3 inactivation through CN-LOH 12q is uniquely associated with B-cell precursor ALL with iAMP21 or other chromosome 21 gain. PMID:30816328

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