Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells.
We report a Jak2V617F knockin mouse myeloproliferative neoplasm (MPN) model resembling human polycythemia vera (PV). The MPN is serially transplantable and we demonstrate that the hematopoietic stem cell (HSC) compartment has the unique capacity for disease initiation but does not have a significant selective competitive advantage over wild-type HSCs. In contrast, myeloid progenitor populations are expanded and skewed toward the erythroid lineage, but cannot transplant the disease. Treatment with a JAK2 kinase inhibitor ameliorated the MPN phenotype, but did not eliminate the disease-initiating population. These findings provide insights into the consequences of JAK2 activation on HSC differentiation and function and have the potential to inform therapeutic approaches to JAK2V617F-positive MPN.
Mullally
Ann
A
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Lane
Steven W
SW
Ball
Brian
B
Megerdichian
Christine
C
Okabe
Rachel
R
Al-Shahrour
Fatima
F
Paktinat
Mahnaz
M
Haydu
J Erika
JE
Housman
Elizabeth
E
Lord
Allegra M
AM
Wernig
Gerlinde
G
Kharas
Michael G
MG
Mercher
Thomas
T
Kutok
Jeffery L
JL
Gilliland
D Gary
DG
Ebert
Benjamin L
BL
D019943:Amino Acid Substitution; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001853:Bone Marrow / Q000473:pathology; D001854:Bone Marrow Cells / Q000187:drug effects; D016026:Bone Marrow Transplantation; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics; D004195:Disease Models, Animal; D015672:Erythroid Precursor Cells / Q000378:metabolism / Q000473:pathology; D004921:Erythropoietin / Q000494:pharmacology; D015870:Gene Expression / Q000235:genetics; D020869:Gene Expression Profiling; D006400:Hematocrit; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006579:Heterozygote; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D055016:Megakaryocyte Progenitor Cells / Q000378:metabolism / Q000473:pathology; D055015:Megakaryocyte-Erythroid Progenitor Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000473:pathology; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D011087:Polycythemia Vera / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D016019:Survival Analysis; D000096926:Benzenesulfonamides
D015703:Antigens, CD; D004921:Erythropoietin; D053614:Janus Kinase 2; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; D013449:Sulfonamides; C528327:fedratinib; D000096926:Benzenesulfonamides; C507926:Jak2 protein, mouse