The Development and Use of Janus Kinase 2 Inhibitors for the Treatment of Myeloproliferative Neoplasms

Gabriela S Hobbs; Sarah Rozelle; Ann Mullally

doi:10.1016/j.hoc.2017.04.002

The Development and Use of Janus Kinase 2 Inhibitors for the Treatment of Myeloproliferative Neoplasms

Hematol Oncol Clin North Am. 2017 Aug;31(4):613-626. doi: 10.1016/j.hoc.2017.04.002. Epub 2017 May 17.

Authors

Gabriela S Hobbs¹, Sarah Rozelle², Ann Mullally³

Affiliations

¹ Division of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: ghobbs@partners.org.
² Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
³ Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: amullally@partners.org.

PMID: 28673391
DOI: 10.1016/j.hoc.2017.04.002

Abstract

Following the discovery of the JAK2V617F mutation, Janus kinase (JAK) 2 inhibitors were developed as rationally designed therapy in myeloproliferative neoplasms (MPNs). Although JAK2 inhibitors have clinical efficacy in MPN, they are not clonally selective for the JAK2V617F-mutant cells. Because activated JAK-signal transducer and activator of transcription (STAT) signaling is a common feature of MPN, JAK2 inhibitors are efficacious regardless of the specific MPN phenotypic driver mutation. The Food and Drug Administration approved the JAK1/JAK2 inhibitor, ruxolitinib, for the treatment of myelofibrosis and polycythemia vera. Additional JAK2 inhibitors are currently in advanced phased clinical trials.

Keywords: JAK-STAT signaling; JAK2 inhibitors; JAK2V617F mutation; Mutant calreticulin; Myelofibrosis; Myeloproliferative neoplasms; Polycythemia vera.

Publication types

Review

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Clinical Trials as Topic
Drug Evaluation, Preclinical
Humans
Janus Kinase 2 / antagonists & inhibitors*
Janus Kinase 2 / chemistry
Janus Kinase 2 / genetics
Janus Kinase 2 / metabolism
Molecular Targeted Therapy*
Mutation
Myeloproliferative Disorders / drug therapy*
Myeloproliferative Disorders / genetics
Myeloproliferative Disorders / metabolism*
Polycythemia Vera / drug therapy
Polycythemia Vera / genetics
Polycythemia Vera / metabolism
Primary Myelofibrosis / drug therapy
Primary Myelofibrosis / genetics
Primary Myelofibrosis / metabolism
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use*
STAT Transcription Factors / metabolism
Signal Transduction / drug effects
Treatment Outcome

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
STAT Transcription Factors
Janus Kinase 2