Combination of New Homozygous MPIG6B and SH2B3 Variants Leads to Early Onset Myelofibrosis, Thrombocytopenia and Abnormal Platelet Function

M.-C. Morel-Kopp^1,2, M. Levade¹, Q. Chen^1,2, A. Livings², J. Curtin³, Y. Zhu⁴, C. Ward^1,2, W. Stevenson^1,2

¹The University of Sydney, Northern Blood Research Centre - Kolling Institute, Sydney, Australia, ²Royal North Shore Hospital, Department of Haematology and Transfusion Medicine, Sydney, Australia, ³The Children's Hospital at Westmead, Department of Haematology, Sydney, Australia, ⁴The University of Sydney, Cancer Genetics Unit - Kolling Institute, Sydney, Australia

Abstract Number: OC 13.3

Meeting: ISTH 2020 Congress

Theme: Platelet Disorders and von Willebrand Disease » Platelet Function Disorders, Hereditary

Background: In 2009, a 9-month old infant from a consanguineous middle-eastern family was diagnosed with infantile myelofibrosis following investigations for splenomegaly, anemia and thrombocytopenia. Despite treatment with oral steroids, he still has evidence of myelofibrosis and platelet dysfunction, but had some improvements in platelet count and splenomegaly.

Aims: To identify a genetic cause for the clinical features and assist with future management.

Methods: Platelet function, biochemistry, signaling and bone marrow biopsies were performed to investigate thrombocytopenia and myelofibrosis. Next-generation sequencing of 343 target genes was conducted.

Results: On examination, hepatosplenomegaly was noted. Stained blood films showed anisocytosis, microcytosis, tear drop poikilocytosis, some target cells and elliptocytes and mild thrombocytopenia with some enlarged and ~30% grey platelets. By western-blotting, total P-selectin content was normal which may suggest in-vivo degranulation. Bone marrow biopsies consistently revealed increased reticulin and collagen fibrosis and the presence of clustered atypical megakaryocytes. Two new homozygous variants were detected; MPIG6B c.A632T, p.Y211F removes the first G6b-B ITIM tyrosine and is predicted to disrupt downstream signaling. Platelet aggregation was markedly reduced with 2ug/ml collagen and 1ug/ml CRP but increased with 2ug/ml CLEC2 antibody. After collagen/CRP stimulation, total phosphorylation was also reduced. Immunoprecipitation experiments suggest that G6b-B Y211 may be more important than Y237 for Shp1 interaction. The second variant, SH2B3 c.G640A, p.G214R, affects the LNK pleckstrin-homology domain and prevents its attachment to the cytoskeleton with consequences on MPL activation pathway (TK signaling) which is always turned on leading to increased basal signaling (phospho-Jak2) and total phosphorylation post-TPO stimulation.

Conclusions: Paediatric thrombocytopenia associated with myelofibrosis is rare and biologically different to adult disease. This is the first case of a child with variants in both MPIG6B and SH2B3 altering platelet signaling and causing thrombocytopenia and myelofibrosis. Severity of thrombocytopenia may be ameliorated by p-Jak/Stat signalling. G6b-B ITIM-Y211 is important for Shp1 interaction and downstream signaling.

To cite this abstract in AMA style:

Morel-Kopp M-, Levade M, Chen Q, Livings A, Curtin J, Zhu Y, Ward C, Stevenson W. Combination of New Homozygous MPIG6B and SH2B3 Variants Leads to Early Onset Myelofibrosis, Thrombocytopenia and Abnormal Platelet Function [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/combination-of-new-homozygous-mpig6b-and-sh2b3-variants-leads-to-early-onset-myelofibrosis-thrombocytopenia-and-abnormal-platelet-function/. Accessed January 28, 2022.

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