title: JAK2 inhibitors do not affect stem cells present in the spleens of patients with myelofibrosis.
abstract: Dysregulation of Janus kinase (JAK)-signal transducer and activator of transcription signaling is central to the pathogenesis of myelofibrosis (MF). JAK2 inhibitor therapy in MF patients results in a rapid reduction of the degree of splenomegaly, yet the mechanism underlying this effect remains unknown. The in vitro treatment of splenic and peripheral blood MF CD34(+) cells with the JAK1/2/3 inhibitor, AZD1480, reduced the absolute number of CD34(+), CD34(+)CD90(+), and CD34(+)CXCR4(+) cells as well as assayable hematopoietic progenitor cells (HPCs) irrespective of the JAK2 and calreticulin mutational status. Furthermore, AZD1480 treatment resulted in only a modest reduction in the proportion of HPCs that were JAK2V617F(+) or had a chromosomal abnormality. To study the effect of the drug on MF stem cells (MF-SCs), splenic CD34(+) cells were treated with AZD1480 and transplanted into immunodeficient mice. JAK2 inhibitor therapy did not affect the degree of human cell chimerism or the proportion of malignant donor cells. These data indicate that JAK2 inhibitor treatment affects a subpopulation of MF-HPCs, while sparing another HPC subpopulation as well as MF-SCs. This pattern of activity might account for the reduction in spleen size observed with JAK2 inhibitor therapy as well as the rapid increase in spleen size observed frequently with its discontinuation.
authors.affiliation: Division of Hematology/Oncology/Pathology, The Tisch Cancer Institute, Department of Medicine, Myeloproliferative Disorders Research Consortium, Icahn School of Medicine at Mount Sinai, New York, NY; and.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Hematology/Oncology/Pathology, The Tisch Cancer Institute, Department of Medicine, Myeloproliferative Disorders Research Consortium, Icahn School of Medicine at Mount Sinai, New York, NY; and.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.affiliation: Division of Hematology/Oncology/Pathology, The Tisch Cancer Institute, Department of Medicine, Myeloproliferative Disorders Research Consortium, Icahn School of Medicine at Mount Sinai, New York, NY; and.
authors.forename: Joseph
authors.initials: J
authors.lastname: Tripodi
authors.affiliation: Division of Hematology/Oncology/Pathology, The Tisch Cancer Institute, Department of Medicine, Myeloproliferative Disorders Research Consortium, Icahn School of Medicine at Mount Sinai, New York, NY; and.
authors.forename: Cing Siang
authors.initials: CS
authors.lastname: Hu
authors.affiliation: Division of Hematology/Oncology/Pathology, The Tisch Cancer Institute, Department of Medicine, Myeloproliferative Disorders Research Consortium, Icahn School of Medicine at Mount Sinai, New York, NY; and.
authors.forename: Jiajing
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Division of Hematology/Oncology/Pathology, The Tisch Cancer Institute, Department of Medicine, Myeloproliferative Disorders Research Consortium, Icahn School of Medicine at Mount Sinai, New York, NY; and.
authors.forename: Vesna
authors.initials: V
authors.lastname: Najfeld
authors.affiliation: Division of Hematology/Oncology/Pathology, The Tisch Cancer Institute, Department of Medicine, Myeloproliferative Disorders Research Consortium, Icahn School of Medicine at Mount Sinai, New York, NY; and.
authors.forename: Jesse
authors.initials: J
authors.lastname: Novak
authors.affiliation: Division of Hematology/Oncology/Pathology, The Tisch Cancer Institute, Department of Medicine, Myeloproliferative Disorders Research Consortium, Icahn School of Medicine at Mount Sinai, New York, NY; and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Raajit
authors.initials: R
authors.lastname: Rampal
authors.affiliation: Division of Hematology/Oncology/Pathology, The Tisch Cancer Institute, Department of Medicine, Myeloproliferative Disorders Research Consortium, Icahn School of Medicine at Mount Sinai, New York, NY; and.
authors.forename: Ronald
authors.initials: R
authors.lastname: Hoffman
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011087:Polycythemia Vera / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000166:cytology*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*; D013922:Thrombocytosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology
chemical_list: C545606:AZD 1480; D011720:Pyrazoles; D011743:Pyrimidines; C507924:JAK2 protein, human; D053614:Janus Kinase 2