The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in Mice that is responsive to therapeutic JAK inhibition

Angela G. Fleischman, Julia Maxson, Samuel B. Luty, Anupriya Agarwal, Lacey R. Royer, Melissa L. Abel, Jason D. Macmaniman, Marc Loriaux, Brian Druker, Jeffrey Tyner

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

We have recently identified targetable mutations in CSF3R (GCSFR) in 60% of chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL-negative) chronic myeloid leukemia (aCML) patients. Here we demonstrate that the most prevalent, activating mutation, CSF3R T618I, is sufficient to drive a lethal myeloproliferative disorder in a murine bone marrow transplantation model. Mice transplanted with CSF3R T618I-expressing hematopoietic cells developed a myeloproliferative disorder characterized by overproduction of granulocytes and granulocytic infiltration ofthe spleen and liver, which was uniformly fatal. Treatment with the JAK1/2 inhibitor ruxolitinib lowered the white blood count and reduced spleen weight. This demonstrates that activating mutations in CSF3R are sufficient to drive a myeloproliferative disorder resembling aCML and CNL that is sensitive to pharmacologic JAK inhibition. This murine model is an excellent tool for the further study of neutrophilic myeloproliferative neoplasms and implicates the clinical use of JAK inhibitors for this disease.

Original languageEnglish (US)
Pages (from-to)3628-3631
Number of pages4
JournalBlood
Volume122
Issue number22
DOIs
StatePublished - Nov 21 2013

Fingerprint

Myeloproliferative Disorders
Leukemia, Neutrophilic, Chronic
Mutation
Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
Spleen
Infiltration
Liver
Neoplasms
Bone
Blood
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Bone Marrow Transplantation
Granulocytes
Therapeutics
Weights and Measures
INCB018424

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in Mice that is responsive to therapeutic JAK inhibition. / Fleischman, Angela G.; Maxson, Julia; Luty, Samuel B.; Agarwal, Anupriya; Royer, Lacey R.; Abel, Melissa L.; Macmaniman, Jason D.; Loriaux, Marc; Druker, Brian; Tyner, Jeffrey.

In: Blood, Vol. 122, No. 22, 21.11.2013, p. 3628-3631.

Research output: Contribution to journalArticle

Fleischman, Angela G. ; Maxson, Julia ; Luty, Samuel B. ; Agarwal, Anupriya ; Royer, Lacey R. ; Abel, Melissa L. ; Macmaniman, Jason D. ; Loriaux, Marc ; Druker, Brian ; Tyner, Jeffrey. / The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in Mice that is responsive to therapeutic JAK inhibition. In: Blood. 2013 ; Vol. 122, No. 22. pp. 3628-3631.
@article{fe2f7c6babe8411991b9bec5ea933990,
title = "The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in Mice that is responsive to therapeutic JAK inhibition",
abstract = "We have recently identified targetable mutations in CSF3R (GCSFR) in 60{\%} of chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL-negative) chronic myeloid leukemia (aCML) patients. Here we demonstrate that the most prevalent, activating mutation, CSF3R T618I, is sufficient to drive a lethal myeloproliferative disorder in a murine bone marrow transplantation model. Mice transplanted with CSF3R T618I-expressing hematopoietic cells developed a myeloproliferative disorder characterized by overproduction of granulocytes and granulocytic infiltration ofthe spleen and liver, which was uniformly fatal. Treatment with the JAK1/2 inhibitor ruxolitinib lowered the white blood count and reduced spleen weight. This demonstrates that activating mutations in CSF3R are sufficient to drive a myeloproliferative disorder resembling aCML and CNL that is sensitive to pharmacologic JAK inhibition. This murine model is an excellent tool for the further study of neutrophilic myeloproliferative neoplasms and implicates the clinical use of JAK inhibitors for this disease.",
author = "Fleischman, {Angela G.} and Julia Maxson and Luty, {Samuel B.} and Anupriya Agarwal and Royer, {Lacey R.} and Abel, {Melissa L.} and Macmaniman, {Jason D.} and Marc Loriaux and Brian Druker and Jeffrey Tyner",
year = "2013",
month = "11",
day = "21",
doi = "10.1182/blood-2013-06-509976",
language = "English (US)",
volume = "122",
pages = "3628--3631",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "22",

}

TY - JOUR

T1 - The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in Mice that is responsive to therapeutic JAK inhibition

AU - Fleischman, Angela G.

AU - Maxson, Julia

AU - Luty, Samuel B.

AU - Agarwal, Anupriya

AU - Royer, Lacey R.

AU - Abel, Melissa L.

AU - Macmaniman, Jason D.

AU - Loriaux, Marc

AU - Druker, Brian

AU - Tyner, Jeffrey

PY - 2013/11/21

Y1 - 2013/11/21

N2 - We have recently identified targetable mutations in CSF3R (GCSFR) in 60% of chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL-negative) chronic myeloid leukemia (aCML) patients. Here we demonstrate that the most prevalent, activating mutation, CSF3R T618I, is sufficient to drive a lethal myeloproliferative disorder in a murine bone marrow transplantation model. Mice transplanted with CSF3R T618I-expressing hematopoietic cells developed a myeloproliferative disorder characterized by overproduction of granulocytes and granulocytic infiltration ofthe spleen and liver, which was uniformly fatal. Treatment with the JAK1/2 inhibitor ruxolitinib lowered the white blood count and reduced spleen weight. This demonstrates that activating mutations in CSF3R are sufficient to drive a myeloproliferative disorder resembling aCML and CNL that is sensitive to pharmacologic JAK inhibition. This murine model is an excellent tool for the further study of neutrophilic myeloproliferative neoplasms and implicates the clinical use of JAK inhibitors for this disease.

AB - We have recently identified targetable mutations in CSF3R (GCSFR) in 60% of chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL-negative) chronic myeloid leukemia (aCML) patients. Here we demonstrate that the most prevalent, activating mutation, CSF3R T618I, is sufficient to drive a lethal myeloproliferative disorder in a murine bone marrow transplantation model. Mice transplanted with CSF3R T618I-expressing hematopoietic cells developed a myeloproliferative disorder characterized by overproduction of granulocytes and granulocytic infiltration ofthe spleen and liver, which was uniformly fatal. Treatment with the JAK1/2 inhibitor ruxolitinib lowered the white blood count and reduced spleen weight. This demonstrates that activating mutations in CSF3R are sufficient to drive a myeloproliferative disorder resembling aCML and CNL that is sensitive to pharmacologic JAK inhibition. This murine model is an excellent tool for the further study of neutrophilic myeloproliferative neoplasms and implicates the clinical use of JAK inhibitors for this disease.

UR - http://www.scopus.com/inward/record.url?scp=84888252332&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84888252332&partnerID=8YFLogxK

U2 - 10.1182/blood-2013-06-509976

DO - 10.1182/blood-2013-06-509976

M3 - Article

VL - 122

SP - 3628

EP - 3631

JO - Blood

JF - Blood

SN - 0006-4971

IS - 22

ER -