The constitutive mobilization of bone marrow-repopulating cells into the peripheral blood in idiopathic myelofibrosis

Idiopathic myelofibrosis (IM) is characterized by the constitutive mobilization of CD34⁺ cells. IM peripheral blood (PB) CD34 ⁺ cells had a reduced cloning efficiency and a lower frequency of cobble-stone areas compared with normal granulocyte colony-stimulating factor (G-CSF)-mobilized PB CD34⁺ cells. IM CD34⁺ cells engrafted nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, demonstrating that they contain bone marrow (BM)-repopulating cells. G-CSF-mobilized CD34⁺ cells produced multiple hematopoietic lineages within the NOD/SCID mice with a predominance of CD19⁺ cells. By contrast, IM CD34⁺ cells produced predominantly CD33⁺ cells, increased numbers of CD41⁺ cells, but fewer CD19⁺ cells. Transcriptional clonality assays of the engrafted human IM cells demonstrated their clonal origin. CD34⁺ cells from one patient isolated prior to leukemic transformation were capable of generating acute leukemia in NOD/SCID mice. The engrafted human cells exhibited the same abnormal karyotype as primary cells in a portion of the population. These findings demonstrate that BM-repopulating cells and more differentiated progenitor cells are constitutively mobilized into the PB in IM, and that their differentiation program Is abnormal. In addition, the MOD/SCID model may be useful in gaining an understanding of the events occurring during the transition of IM to acute leukemia.