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Overview of Transgenic Mouse Models of Myeloproliferative Neoplasms (MPNs).

Abstract Myeloproliferative neoplasms (MPNs) are a class of hematologic diseases characterized by aberrant proliferation of one or more myeloid lineages and progressive bone marrow fibrosis. In 2005, seminal work by multiple groups identified the JAK2V617F mutation in a significant fraction of MPN patients. Since that time, murine models of JAK2V617F have greatly enhanced the understanding of the role of aberrant JAK-STAT signaling in MPN pathogenesis and have provided an in vivo pre-clinical platform that can be used to develop novel therapies. From early retroviral transduction models to transgenics, and ultimately conditional knock-ins, murine models have established that JAK2V617F alone can induce an MPN-like syndrome in vivo. However, additional mutations co-occur with JAK2V617F in MPNs, often in proteins involved in epigenetic regulation that can dramatically influence disease outcomes. In vivo modeling of these mutations in the context of JAK2V617F has provided additional insights into the role of epigenetic dysregulation in augmenting MPN hematopoiesis. In this overview, early murine model development of JAK2V617F is described, with an analysis of its effects on the hematopoietic stem/progenitor cell niche and interactions with downstream signaling elements. This is followed by a description of more recent in vivo models developed for evaluating the effect of concomitant mutations in epigenetic modifiers on MPN maintenance and progression. Mouse models of other driver mutations in MPNs, including primarily calreticulin (CALR) and Tpo-receptor (MPL), which occur in a significant percentage of MPN patients with wild-type JAK2, are also briefly reviewed. © 2017 by John Wiley & Sons, Inc.
PMID
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Not Available.

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Authors

Mayor MeshTerms

Disease Models, Animal

Keywords

JAK2

epigenetics

leukemia

myeloproliferative neoplasms

Journal Title current protocols in pharmacology
Publication Year Start




PMID- 28640953
OWN - NLM
STAT- MEDLINE
DA  - 20170622
DCOM- 20170714
LR  - 20170714
IS  - 1934-8290 (Electronic)
IS  - 1934-8282 (Linking)
VI  - 77
DP  - 2017 Jun 22
TI  - Overview of Transgenic Mouse Models of Myeloproliferative Neoplasms (MPNs).
PG  - 14.40.1-14.40.19
LID - 10.1002/cpph.23 [doi]
AB  - Myeloproliferative neoplasms (MPNs) are a class of hematologic diseases
      characterized by aberrant proliferation of one or more myeloid lineages and
      progressive bone marrow fibrosis. In 2005, seminal work by multiple groups
      identified the JAK2V617F mutation in a significant fraction of MPN patients.
      Since that time, murine models of JAK2V617F have greatly enhanced the
      understanding of the role of aberrant JAK-STAT signaling in MPN pathogenesis and 
      have provided an in vivo pre-clinical platform that can be used to develop novel 
      therapies. From early retroviral transduction models to transgenics, and
      ultimately conditional knock-ins, murine models have established that JAK2V617F
      alone can induce an MPN-like syndrome in vivo. However, additional mutations
      co-occur with JAK2V617F in MPNs, often in proteins involved in epigenetic
      regulation that can dramatically influence disease outcomes. In vivo modeling of 
      these mutations in the context of JAK2V617F has provided additional insights into
      the role of epigenetic dysregulation in augmenting MPN hematopoiesis. In this
      overview, early murine model development of JAK2V617F is described, with an
      analysis of its effects on the hematopoietic stem/progenitor cell niche and
      interactions with downstream signaling elements. This is followed by a
      description of more recent in vivo models developed for evaluating the effect of 
      concomitant mutations in epigenetic modifiers on MPN maintenance and progression.
      Mouse models of other driver mutations in MPNs, including primarily calreticulin 
      (CALR) and Tpo-receptor (MPL), which occur in a significant percentage of MPN
      patients with wild-type JAK2, are also briefly reviewed. (c) 2017 by John Wiley &
      Sons, Inc.
CI  - Copyright (c) 2017 John Wiley & Sons, Inc.
FAU - Dunbar, Andrew
AU  - Dunbar A
AD  - Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center,
      New York City, New York.
FAU - Nazir, Abbas
AU  - Nazir A
AD  - Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center,
      New York City, New York.
FAU - Levine, Ross
AU  - Levine R
AD  - Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center,
      New York City, New York.
AD  - Leukemia Service Department of Medicine, Memorial Sloan Kettering Cancer Center, 
      New York City, New York.
AD  - Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York
      City, New York.
AD  - Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New 
      York City, New York.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20170622
PL  - United States
TA  - Curr Protoc Pharmacol
JT  - Current protocols in pharmacology
JID - 9717249
RN  - 0 (Calreticulin)
RN  - 0 (Receptors, Thrombopoietin)
RN  - 0 (STAT Transcription Factors)
RN  - 0 (calreticulin, human)
RN  - EC 2.7.10.2 (JAK2 protein, human)
RN  - EC 2.7.10.2 (Janus Kinase 2)
SB  - IM
MH  - Animals
MH  - Calreticulin/genetics/metabolism
MH  - Cell Line, Tumor
MH  - *Disease Models, Animal
MH  - Epigenesis, Genetic
MH  - Gene Knock-In Techniques
MH  - Hematopoietic Stem Cells/metabolism/physiology
MH  - Humans
MH  - Janus Kinase 2/*genetics/*metabolism
MH  - Leukemia/*genetics/metabolism/prevention & control
MH  - Mice, Transgenic
MH  - Mutation
MH  - Myeloproliferative Disorders/*genetics
MH  - Receptors, Thrombopoietin/genetics/metabolism
MH  - STAT Transcription Factors/metabolism
MH  - Signal Transduction
OTO - NOTNLM
OT  - JAK2
OT  - epigenetics
OT  - leukemia
OT  - myeloproliferative neoplasms
EDAT- 2017/06/24 06:00
MHDA- 2017/07/15 06:00
CRDT- 2017/06/23 06:00
AID - 10.1002/cpph.23 [doi]
PST - epublish
SO  - Curr Protoc Pharmacol. 2017 Jun 22;77:14.40.1-14.40.19. doi: 10.1002/cpph.23.