The JAK–STAT pathway is a rapid signal transduction pathway that controls cell growth, survival, and maturation. [5] In blood-forming cells, hormones such as erythropoietin (EPO) use this route to regulate red blood cell production. When the signaling is precisely regulated, erythropoiesis is maintained in alignment with the body’s physiological demands. [6]

Why cells use it >> to control growth, survival, and maturation.

When the signaling is precisely regulated, erythropoiesis is maintained in alignment with the body’s physiological demands. [2][7]

You can think of the JAK–STAT pathway as the way a cell receives and acts on important “messages.”[8] The cytokine is lie a message. It docks to its matching receptor, which activates helper proteins called JAKs. JAKs then switch on STATs. The STATs pair up, move into the cell’s control room (the nucleus), and turn certain genes up or down. [6]

In PV, JAK2 changes can keep the JAK-STAT pathway active without the usual “on/off” checks. When EPO receptor signaling persists through the JAK-STAT pathway, red blood cell precursors multiply and survive longer than they should, thereby increasing red blood cell mass and hematocrit levels. The result is thicker blood and thromboses. [4][9]

This persistent JAK-STAT pathway activity can also influence white blood cells and platelets, which is why some people experience broader count elevations, in addition to red blood cell elevations. The key idea is that when the JAK-STAT pathway is “on,” the marrow’s output rises above the healthy range, and everyday symptoms often track with that overproduction. [4]

In blood-forming cells, hormones such as erythropoietin (EPO) and thrombopoietin signal through receptors associated with JAK2 to activate the JAK–STAT pathway. When the cytokine engages its receptor, it induces conformational changes that activate the associated JAK2 proteins through transphosphorylation. Activated JAK2 then creates phosphorylated sites on the receptor that recruit STAT proteins, commonly STAT5. These STATs are phosphorylated, dimerize, translocate into the nucleus, and regulate genes involved in cell growth and survival. [2]

Under normal conditions, built-in brakes, such as uppressor of cytokine signaling (SOCS) proteins and phosphatases, dampen the activity of JAK2 and STAT proteins, helping to switch the signal off. In polycythemia vera, JAK2-driven signaling can persist, keeping certain parts of the JAK-STAT pathway active longer than intended and promoting excessive red blood cell production. [7][8]

When the JAK-STAT pathway remains active in PV, blood cell production increases, and blood becomes thicker (hyperviscosity), which helps explain common symptoms like headaches, dizziness, and visual blurring. Elevated platelets can contribute to microvascular symptoms (e.g., tingling in fingers/toes, headache, pruritus), reflecting persistent signals that travel through the JAK-STAT pathway. Aquagenic itch is a common JAK2 mutation-related symptom. [10]

JAK-STAT pathway inhibitors are a class of small-molecule drugs that block the Janus kinase (JAK)-STAT signaling pathway, which is involved in immune responses and cellular growth [11]. These inhibitors reduce signal flow through the pathway, so fewer growth messages reach the nucleus.

1. Is the JAK-STAT pathway the same across PV, ET, and MF?

The core relay is the same, but different driver mutations (for example, JAK2, CALR, MPL) can converge on activated JAK–STAT signaling across these MPNs. [12] Gene expression signatures consistent with JAK2 pathway activation are observed across MPNs. [13]

2. The JAK-STAT pathway plays a critical role in PV. Does this mean that only the JAK–STAT pathway matters in PV?

No, EPO signaling also engages PI3K–AKT and MAPK cascades alongside JAK–STAT, and these routes can interact. JAK–STAT is central to erythroid survival and proliferation, but it is part of a broader network. [14]

3. What turns the JAK-STAT signaling pathway off under normal conditions?

The JAK-STAT pathway is normally turned off by several built-in brakes, including tyrosine phosphatases, receptor internalization, and inhibitory proteins such as Suppressor of Cytokine Signaling (SOCS) and Protein Inhibitor of Activated STAT (PIAS). These mechanisms work together in negative-feedback loops that dampen signaling and limit how long the pathway stays active. [12]

4. Do JAK-STAT pathway inhibitors block STAT directly?

No, most JAK-STAT pathway inhibitors do not block STAT directly; instead, they primarily target the JAK enzymes to prevent STAT from being phosphorylated. By blocking the Janus kinases (JAKs), these inhibitors stop the initial activation step, which in turn prevents STATs from becoming phosphorylated, forming dimers, and moving to the nucleus to regulate gene expression. [15]

5. Is the JAK-STAT pathway always active in PV?

Constitutive pathway activation is a hallmark of PV biology, especially with JAK2 V617F mutation. The unifying feature is abnormally persistent signaling compared with normal erythropoiesis. [16]

6. Where does JAK2 sit in the pathway for red cell production?

At the EPO receptor. EPOR activates JAK2, which phosphorylates STAT5. STAT5 dimers then enter the nucleus to drive genes that support erythroid survival and proliferation. [17]

• AKT – A serine/threonine kinase involved in cell survival and metabolism; part of the PI3K–AKT pathway
• CALR – Calreticulin; mutations in this gene activate JAK–STAT signaling in some MPNs
• DNA – Deoxyribonucleic acid
• EPO – Erythropoietin; hormone that regulates red blood cell production
• EPOR – Erythropoietin receptor; activates JAK2 when EPO binds
• ET – Essential thrombocythemia
• JAK – Janus kinase; intracellular tyrosine kinases that transmit signals from cytokine receptors
• JAK2 V617F – The most common JAK2 mutation in PV, causing constitutive JAK–STAT activation
• MAPK – Mitogen-activated protein kinase; a parallel pathway engaged by cytokine receptors
• MF – Myelofibrosis
• MPN – Myeloproliferative neoplasm
• PI3K – Phosphoinositide 3-kinase; upstream activator of AKT
• PV – Polycythemia vera
• SOCS – Suppressor of cytokine signaling; proteins that negatively regulate the JAK–STAT pathway
• STAT – Signal transducer and activator of transcription; transcription factors activated by JAKs
• TPO – Thrombopoietin; hormone regulating platelet production
• TPOR/MPL – Thrombopoietin receptor (also known as MPL), signals through JAK2
• WBC – White blood cell
• PIAS – Protein Inhibitor of Activated STAT

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