title: Spleens of myelofibrosis patients contain malignant hematopoietic stem cells.
abstract: Cancer stem cell behavior is thought to be largely determined by intrinsic properties and by regulatory signals provided by the microenvironment. Myelofibrosis (MF) is characterized by hematopoiesis occurring not only in the marrow but also in extramedullary sites such as the spleen. In order to study the effects of these different microenvironments on primitive malignant hematopoietic cells, we phenotypically and functionally characterized splenic and peripheral blood (PB) MF CD34+ cells from patients with MF. MF spleens contained greater numbers of malignant primitive HPCs than PB. Transplantation of PB MF CD34+ cells into immunodeficient (NOD/SCID/IL2Rγ(null)) mice resulted in a limited degree of donor cell chimerism and a differentiation program skewed toward myeloid lineages. By contrast, transplanted splenic MF CD34+ cells achieved a higher level of chimerism and generated both myeloid and lymphoid cells that contained molecular or cytogenetic abnormalities indicating their malignant nature. Only splenic MF CD34+ cells were able to sustain hematopoiesis for prolonged periods (9 months) and were able to engraft secondary recipients. These data document the existence of MF stem cells (MF-SCs) that reside in the spleens of MF patients and demonstrate that these MF-SCs retain a differentiation program identical to that of normal hematopoietic stem cells.
authors.affiliation: Division of Hematology/Oncology, Pathology and Surgery, Tisch Cancer Institute, Myeloproliferative Disorders Research Consortium, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.forename: Sonam
authors.initials: S
authors.lastname: Prakash
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Joseph
authors.initials: J
authors.lastname: Tripodi
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Vesna
authors.initials: V
authors.lastname: Najfeld
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Myron
authors.initials: M
authors.lastname: Schwartz
authors.forename: Rona
authors.initials: R
authors.lastname: Weinberg
authors.forename: Paul
authors.initials: P
authors.lastname: Roda
authors.forename: Attilio
authors.initials: A
authors.lastname: Orazi
authors.forename: Ronald
authors.initials: R
authors.lastname: Hoffman
mesh_terms: D000368:Aged; D000818:Animals; D018952:Antigens, CD34; D005260:Female; D006411:Hematopoiesis, Extramedullary; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D036102:Peripheral Blood Stem Cell Transplantation; D055728:Primary Myelofibrosis / Q000378:metabolism* / Q000473:pathology; D013154:Spleen / Q000378:metabolism* / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D018952:Antigens, CD34