JAKs to STATs: A tantalizing therapeutic target in acute myeloid leukemia

Sangeetha Venugopal; Michal Bar-Natan; John O Mascarenhas

doi:10.1016/j.blre.2019.100634

JAKs to STATs: A tantalizing therapeutic target in acute myeloid leukemia

Blood Rev. 2020 Mar:40:100634. doi: 10.1016/j.blre.2019.100634. Epub 2019 Oct 25.

Authors

Sangeetha Venugopal¹, Michal Bar-Natan², John O Mascarenhas³

Affiliations

¹ Tisch Cancer Institute, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1079, New York, NY 10029, USA. Electronic address: sangeetha.venugopal@mountsinai.org.
² Tisch Cancer Institute, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1079, New York, NY 10029, USA. Electronic address: michal.bar-natan@mssm.edu.
³ Tisch Cancer Institute, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1079, New York, NY 10029, USA. Electronic address: john.mascarenhas@mssm.edu.

PMID: 31677846
DOI: 10.1016/j.blre.2019.100634

Abstract

The Janus Associated Kinase-Signal Transducers and Activators of Transcription (JAK-STAT) signaling pathway plays a pivotal role in hematopoietic growth factor signaling. Hyperactive JAK-STAT signaling is implicated in the pathogenesis of myeloid malignancies, including acute myeloid leukemia (AML). The significant headway in understanding the biology of AML has led to an explosion of novel therapeutics with mechanistic rationale for the treatment of newly diagnosed and relapsed/refractory (R/R) AML. Most importantly, selective targeting of the JAK-STAT pathway has proven to be an effective therapeutic strategy in myeloproliferative neoplasms and is also being evaluated in related myeloid malignancies, including AML. This comprehensive review will focus on the apparent and evolving potential of JAK-STAT pathway inhibition in AML with emphasis on JAK inhibitors, highlighting both success and failure with this experimental approach in the clinic, and identifying rationally based combinatorial approaches.

Keywords: Acute myeloid leukemia; JAK-STAT; Ruxolitinib,fedratinib.

Publication types

Review

MeSH terms

Drug Delivery Systems*
Humans
Janus Kinases* / antagonists & inhibitors
Janus Kinases* / genetics
Janus Kinases* / metabolism
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / enzymology
Leukemia, Myeloid, Acute* / genetics
Neoplasm Proteins* / antagonists & inhibitors
Neoplasm Proteins* / genetics
Neoplasm Proteins* / metabolism
Phosphorylation / drug effects
Phosphorylation / genetics
STAT Transcription Factors* / antagonists & inhibitors
STAT Transcription Factors* / genetics
STAT Transcription Factors* / metabolism
Signal Transduction / drug effects
Signal Transduction / genetics

Substances

Neoplasm Proteins
STAT Transcription Factors
Janus Kinases