Abstract
SH2B3 encodes LNK protein, a negative regulator of JAK-STAT and RTK signaling. Pathogenic loss-of-function bi-allelic germline variants in SH2B3 are extremely rare and predispose to acute lymphoblastic leukemia (ALL), juvenile myelomonocytic leukemia (JMML), liver cirrhosis, and autoimmunity (Perez-Garcia et al, 2013; Blombery et al, 2023). We report a 16-year-old girl diagnosed at age 12 years with high-risk B-ALL (CNS-1) characterized by hyperdiploidy (trisomies 4, 9, 14, and X), two additional copies of RUNX1, monosomy of E2A, and CDKN2A deletion. BCR-ABL1 was negative. Past medical history was remarkable for juvenile rheumatoid arthritis, celiac disease, hypogonadotropic hypogonadism, short stature, delayed puberty, and a repaired atrial septal defect. Ultrasound abdomen showed an irregular liver surface and splenomegaly with features of portal hypertension. There was no significant hepatic iron deposition on T2*-weighted liver MRI. Liver biopsy confirmed advanced fibrosis, stage 4a (Laennec). Infectious disease workup for hepatitis was negative.
The patient achieved complete remission (CR1) after induction using AALL0232 protocol and completed therapy in February 2024. The patient suffered an isolated marrow relapse in April 2024, again demonstrating hyperdiploidy and two additional copies of RUNX1. Salvage reinduction followed by three cycles of blinatumomab resulted in CR2; hematopoietic stem cell transplantation (HSCT) is planned but deferred due to advanced liver disease.
Germline whole-exome sequencing identified a homozygous SH2B3 frameshift variant c.1038dup; p.(Leu347Alafs*38) initially classified as VUS but recently reclassified as pathogenic in a JMML cohort (Arfeuille et al, 2023). Deletions of SH2B3 are frequent in iAMP21 high-risk B-ALL subtype (Baughn et al, 2018). Although classical iAMP21 involves three or more extra RUNX1 copies, our patient had two additional copies of RUNX1, which were also present at the time of relapse.
Ruxolitinib (JAK1/2 inhibitor) might be effective in this disorder given the enhanced JAK-STAT signaling. Limited reports have been published about its potential efficacy (Wintering et al, 2024). Given that our patient is not fit for HSCT, ruxolitinib was initiated in addition to maintenance chemotherapy with no excess toxicity. We propose long-term use to reduce relapse risk. HSCT should be considered at a younger age, prior to the onset of liver cirrhosis.
This case further elucidates the role of SH2B3 in leukemogenesis and supports for screening of SH2B3 variants in patients with ALL and gain of RUNX1. Future research is necessary to identify the optimal treatments for this condition, including the potential use of JAK inhibitors.
