JAK2
The signalling enzyme that tells marrow cells to make red cells and platelets; a single mutation (V617F) leaves it switched on in most myeloproliferative neoplasms.
Janus kinase 2 transduces signals from EPO, TPO and GM-CSF receptors via STAT5. JAK2 V617F (2005) is present in ~95% of polycythaemia vera and ~60% of essential thrombocythaemia and primary myelofibrosis; CALR and MPL mutations activate the same pathway. Approved JAK inhibitors (ruxolitinib, fedratinib, pacritinib, momelotinib) inhibit wild-type and mutant JAK2 alike, controlling symptoms and spleen without eliminating the clone. Mutant-selective (V617F pseudokinase) and type II inhibitors are in development. JAK2 fusions and mutations also occur in ALL (Ph-like) and Down-syndrome ALL.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
In plain words · The signalling enzyme that tells marrow cells to make red cells and platelets; a single mutation (V617F) leaves it switched on in most myeloproliferative neoplasms.
- 1 · What it is
The signalling enzyme that tells marrow cells to make red cells and platelets; a single mutation (V617F) leaves it switched on in most myeloproliferative neoplasms.
- 2 · What goes wrong in cancer
JAK2 is a non-receptor tyrosine kinase with a pseudokinase (JH2) domain that normally restrains the kinase (JH1); V617F in JH2 relieves autoinhibition, causing cytokine-independent STAT5/MAPK/PI3K signalling and erythroid/megakaryocytic expansion.
- 3 · How drugs use it
5 products aim at JAK2: small molecules and other agents. Kinases are switched on by binding ATP inside the cell, so most drugs are small molecules shaped to plug that ATP pocket.
Biology
JAK2 is a non-receptor tyrosine kinase with a pseudokinase (JH2) domain that normally restrains the kinase (JH1); V617F in JH2 relieves autoinhibition, causing cytokine-independent STAT5/MAPK/PI3K signalling and erythroid/megakaryocytic expansion.
- Polycythaemia vera (~95% V617F, ~3% exon 12)
- Essential thrombocythaemia and primary myelofibrosis (~55-65%)
- Ph-like B-ALL (JAK2 fusions, ~7%)
- Down syndrome ALL (JAK2 R683)
How common it is, by cancer
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Myeloproliferative neoplasms | 60-95% | JAK2 V617F by subtype | doi.org |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
A second JAK inhibitor for myelofibrosis that works after ruxolitinib fails; it carries a boxed warning for a rare brain toxicity (Wernicke encephalopathy) so thiamine is checked.
Momelotinib is the JAK inhibitor designed for anaemic myelofibrosis patients: it can improve haemoglobin while shrinking the spleen.
The JAK inhibitor for myelofibrosis patients whose platelet counts are too low for ruxolitinib.
Ropeginterferon alfa-2b is a long-acting interferon for polycythaemia vera that, unlike hydroxyurea, can shrink the mutant clone over years.
Ruxolitinib was the first JAK inhibitor: it shrinks the spleen and relieves symptoms in myelofibrosis and controls blood counts in polycythaemia vera, without eliminating the disease clone.
MOMENTUM addressed the biggest gap left by ruxolitinib: patients whose anaemia makes standard JAK inhibition hard to give. Momelotinib is now the preferred option for anaemic, previously treated myelofibrosis and is being adopted in first line for anaemic patients. The absolute symptom benefit is modest and durable disease modification has not been shown.
COMFORT-I turned the 2005 discovery of the JAK2 V617F mutation into the first effective medicine for myelofibrosis, transforming symptom control for a disease with no prior standard. Ruxolitinib is still the reference first-line therapy, with fedratinib, pacritinib and momelotinib as alternatives for cytopenic patients. It does not eliminate the malignant clone or reverse fibrosis in most patients.
Latest papers
topQuery for this target: (TITLE:"JAK2" OR ABSTRACT:"JAK2") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about JAK2, not a curated reading list.
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