Conditional Deletion of Jak2 Reveals an Essential Role in Hematopoiesis throughout Mouse Ontogeny: Implications for Jak2 Inhibition in Humans

Sung O. Park, Heather L. Wamsley, Kyungmi Bae, Zhongbo Hu, Xiaomiao Li, Se woon Choe, William B. Slayton, S. Paul Oh, Kay Uwe Wagner, Peter P. Sayeski

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Germline deletion of Jak2 in mice results in embryonic lethality at E12.5 due to impaired hematopoiesis. However, the role that Jak2 might play in late gestation and postnatal life is unknown. To understand this, we utilized a conditional knockout approach that allowed for the deletion of Jak2 at various stages of prenatal and postnatal life. Specifically, Jak2 was deleted beginning at either mid/late gestation (E12.5), at postnatal day 4 (PN4), or at ~2 months of age. Deletion of Jak2 beginning at E12.5 resulted in embryonic death characterized by a lack of hematopoiesis. Deletion beginning at PN4 was also lethal due to a lack of erythropoiesis. Deletion of Jak2 in young adults was characterized by blood cytopenias, abnormal erythrocyte morphology, decreased marrow hematopoietic potential, and splenic atrophy. However, death was observed in only 20% of the mutants. Further analysis of these mice suggested that the increased survivability was due to an incomplete deletion of Jak2 and subsequent re-population of Jak2 expressing cells, as conditional deletion in mice having one floxed Jak2 allele and one null allele resulted in a more severe phenotype and subsequent death of all animals. We found that the deletion of Jak2 in the young adults had a differential effect on hematopoietic lineages; specifically, conditional Jak2 deletion in young adults severely impaired erythropoiesis and thrombopoiesis, modestly affected granulopoiesis and monocytopoiesis, and had no effect on lymphopoiesis. Interestingly, while the hematopoietic organs of these mutant animals were severely affected by the deletion of Jak2, we found that the hearts, kidneys, lungs, and brains of these same mice were histologically normal. From this, we conclude that Jak2 plays an essential and non-redundant role in hematopoiesis during both prenatal and postnatal life and this has direct implications regarding the inhibition of Jak2 in humans.

Original languageEnglish (US)
Article numbere59675
JournalPloS one
Volume8
Issue number3
DOIs
StatePublished - Mar 27 2013

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hematopoiesis
Hematopoiesis
ontogeny
Animals
young adults
Young Adult
erythropoiesis
Erythropoiesis
mice
Brain
Abnormal Erythrocytes
Blood
Alleles
pregnancy
Lymphopoiesis
Thrombopoiesis
death
Animal Structures
Pregnancy
mutants

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Conditional Deletion of Jak2 Reveals an Essential Role in Hematopoiesis throughout Mouse Ontogeny : Implications for Jak2 Inhibition in Humans. / Park, Sung O.; Wamsley, Heather L.; Bae, Kyungmi; Hu, Zhongbo; Li, Xiaomiao; Choe, Se woon; Slayton, William B.; Oh, S. Paul; Wagner, Kay Uwe; Sayeski, Peter P.

In: PloS one, Vol. 8, No. 3, e59675, 27.03.2013.

Research output: Contribution to journalArticle

Park, SO, Wamsley, HL, Bae, K, Hu, Z, Li, X, Choe, SW, Slayton, WB, Oh, SP, Wagner, KU & Sayeski, PP 2013, 'Conditional Deletion of Jak2 Reveals an Essential Role in Hematopoiesis throughout Mouse Ontogeny: Implications for Jak2 Inhibition in Humans', PloS one, vol. 8, no. 3, e59675. https://doi.org/10.1371/journal.pone.0059675
Park, Sung O. ; Wamsley, Heather L. ; Bae, Kyungmi ; Hu, Zhongbo ; Li, Xiaomiao ; Choe, Se woon ; Slayton, William B. ; Oh, S. Paul ; Wagner, Kay Uwe ; Sayeski, Peter P. / Conditional Deletion of Jak2 Reveals an Essential Role in Hematopoiesis throughout Mouse Ontogeny : Implications for Jak2 Inhibition in Humans. In: PloS one. 2013 ; Vol. 8, No. 3.
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abstract = "Germline deletion of Jak2 in mice results in embryonic lethality at E12.5 due to impaired hematopoiesis. However, the role that Jak2 might play in late gestation and postnatal life is unknown. To understand this, we utilized a conditional knockout approach that allowed for the deletion of Jak2 at various stages of prenatal and postnatal life. Specifically, Jak2 was deleted beginning at either mid/late gestation (E12.5), at postnatal day 4 (PN4), or at ~2 months of age. Deletion of Jak2 beginning at E12.5 resulted in embryonic death characterized by a lack of hematopoiesis. Deletion beginning at PN4 was also lethal due to a lack of erythropoiesis. Deletion of Jak2 in young adults was characterized by blood cytopenias, abnormal erythrocyte morphology, decreased marrow hematopoietic potential, and splenic atrophy. However, death was observed in only 20{\%} of the mutants. Further analysis of these mice suggested that the increased survivability was due to an incomplete deletion of Jak2 and subsequent re-population of Jak2 expressing cells, as conditional deletion in mice having one floxed Jak2 allele and one null allele resulted in a more severe phenotype and subsequent death of all animals. We found that the deletion of Jak2 in the young adults had a differential effect on hematopoietic lineages; specifically, conditional Jak2 deletion in young adults severely impaired erythropoiesis and thrombopoiesis, modestly affected granulopoiesis and monocytopoiesis, and had no effect on lymphopoiesis. Interestingly, while the hematopoietic organs of these mutant animals were severely affected by the deletion of Jak2, we found that the hearts, kidneys, lungs, and brains of these same mice were histologically normal. From this, we conclude that Jak2 plays an essential and non-redundant role in hematopoiesis during both prenatal and postnatal life and this has direct implications regarding the inhibition of Jak2 in humans.",
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