Related Experiment Video

Updated: Feb 15, 2026

Transduction-Transplantation Mouse Model of Myeloproliferative Neoplasm
08:12

Transduction-Transplantation Mouse Model of Myeloproliferative Neoplasm

Published on: December 22, 2016

12.5K

JAK2/IDH-mutant-driven myeloproliferative neoplasm is sensitive to combined targeted inhibition

Anna Sophia McKenney1,2,3, Allison N Lau4, Amritha Varshini Hanasoge Somasundara3

  • 1Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, New York, USA.

The Journal of Clinical Investigation
|January 23, 2018
PubMed

Insights

Combining JAK and IDH inhibition therapies may treat high-risk myeloproliferative neoplasms (MPNs). This approach normalized stem cell function and reduced disease burden in mice and patient cells.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Myeloproliferative neoplasms (MPNs) can progress to bone marrow failure or acute myeloid leukemia (AML).
  • Mutations in epigenetic regulators like isocitrate dehydrogenase (IDH) are linked to poor MPN outcomes.
  • Concurrent mutations in JAK2 and IDH are observed in high-risk MPN patients.

Purpose of the Study:

  • To investigate the impact of combined JAK2 and IDH mutations on MPN development and progression.
  • To evaluate the therapeutic potential of combined JAK2 and IDH inhibition in MPN models.

Main Methods:

  • Utilized a murine model with combined Jak2V617F and mutant IDH1R132H or Idh2R140Q expression.
  • Assessed the efficacy of small-molecule inhibitors targeting IDH and JAK2.
  • Analyzed stem/progenitor cell function, differentiation, gene expression, and metabolite profiles.
  • Tested combined inhibitor efficacy in patient-derived cells with concurrent JAK2 and IDH2 mutations.

Main Results:

  • Combined Jak2V617F and Idh2R140Q mutations induced MPN progression, altered stem/progenitor cell function, and impaired differentiation in mice.
  • MPNs driven by Jak2V617F and Idh2R140Q mutations responded to IDH inhibition.
  • Combined JAK2 and IDH2 inhibition normalized stem/progenitor cell compartments and reduced disease burden more effectively than JAK inhibition alone.
  • Combined therapy reversed aberrant gene expression and metabolite perturbations in MPN stem cells.
  • Cooperative efficacy was observed in patient cells with concurrent JAK2 and IDH2 mutations.

Conclusions:

  • Combined JAK and IDH inhibition demonstrates therapeutic potential for high-risk MPN subtypes with concurrent mutations.
  • This dual-targeting strategy offers a promising approach to normalize cellular function and reduce disease burden in MPNs.
Keywords:
Drug therapyHematologyLeukemiasOncology

More Related Videos

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids08:52

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids

Published on: November 22, 2021

4.7K
High-Throughput Robotically Assisted Isolation of Temperature-sensitive Lethal Mutants in Chlamydomonas reinhardtii10:51

High-Throughput Robotically Assisted Isolation of Temperature-sensitive Lethal Mutants in Chlamydomonas reinhardtii

Published on: December 5, 2016

10.4K

Related Concept Videos

Feedback Inhibition00:46

Feedback Inhibition

Biochemical reactions are occurring constantly in cells, converting starting substances to different products, usually with the help of enzymes that speed the reactions. Without enzymes, it would take far too long for most reactions to occur to be useful to the cell!
57.4K
Enzyme Inhibition01:30

Enzyme Inhibition

Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
92.9K
ATP Driven Pumps I: An Overview01:27

ATP Driven Pumps I: An Overview

ATP-driven pumps, also known as transport ATPases, are integral membrane proteins. They have binding sites for ATP located on the membrane's cytosolic side and the ion-conducting domain in the transmembrane region. These pumps use the free energy released from ATP hydrolysis to move the solutes across cell membranes against an electrochemical gradient.
There are four main types of ATP-driven pumps - P-type, V-type, F-type, and ABC transporter. All these pumps are of varying complexities and...
10.0K
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
6.0K
Xylem and Transpiration-driven Transport of Resources02:03

Xylem and Transpiration-driven Transport of Resources

The xylem of vascular plants distributes water and dissolved minerals that are taken up by the roots to the rest of the plant. The cells that transport xylem sap are dead upon maturity, and the movement of xylem sap is a passive process.
27.0K
ATP Driven Pumps II: P-type Pumps01:34

ATP Driven Pumps II: P-type Pumps

The P-type pumps are a large family of integral membrane transporter ATPases. They are divided into five major types based on substrate specificity, from I to V.
A typical P-type pump has three cytosolic domains: nucleotide-binding (N), phosphorylation (P), and activator (A) domains. These domains are connected to the membrane-spanning helices by short amino acid segments. ATP hydrolysis and covalent phosphoenzyme intermediate formation are crucial parts of the catalytic cycle. At the highly...
6.5K