In both humans and mice, megakaryocytes that express a functional form of G6b-B (A) reside in a bone marrow environment that contains normal levels of extracellular matrix proteins. Phosphorylation of tyrosine residues (pY) within G6b-B ITIM and ITSM motifs enables recruitment and activation of Shp1 and/or Shp2, which are required for production of normal numbers of properly functioning platelets. Megakaryocytes that do not express G6b-B or that express a dysfunctional form of G6b-B that cannot be tyrosine phosphorylated (G6b-B di-Y/F; B) form clusters in a fibrotic bone marrow environment and produce low numbers of large, dysfunctional platelets. These findings demonstrate that the signaling capabilities of G6b-B play an important role in regulating platelet number and function, and identify pathogenic variants in the gene that encodes G6b-B as a cause of inherited myelofibrosis. Figure design was inspired by Leiva et al.¹³