Hypothesis of novel Notch signaling in the BM during normal hematopoiesis and myeloproliferative disease. (A) Schematic representation of possible Notch/Notch ligand interactions in the BM: (1) BM microenvironment-HSC, (2) HSC-HSC, (3) HSC-progeny, and (4) BM microenvironment-BM microenvironment. (B) Proposed novel Notch signaling in the BM microenvironment. Mib1 regulates Notch ligands, such as Jag1, Jag2, or Dll1, in BM microenvironmental cells to send Notch signaling into other BM microenvironmental cells. In the Notch signal-receiving BM microenvironmental cells, Notch signaling activated by Presenilin1/2 is transduced to Rbp-jκ or Deltex, and eventually turns on the transcription of target genes. Unknown signaling pathways from the wild-type BM microenvironment control HSCs to maintain normal hematopoiesis. In the Mib1-null BM microenvironment, however, defective Notch activation between the BM microenvironmental cells causes the HSCs to become myeloproliferative through an unidentified mechanism.