• What is JAK2?
  • JAK2 in Myeloproliferative Neoplasms
  • JAK2 c.1624_1629delAATGAA (N542_E543del)
  • Clinical Trials


Janus kinase 2 (JAK2) encodes for a protein tyrosine kinase involved in cytokine receptor signaling. Mutations in JAK2 have been identified in ALL and other hematologic malignancies.

Preclinical models have been used to test efficacy of mTOR and JAK inhibitors in CRLF2-rearranged and JAK2-mutated high-risk precursor B-cell ALL (Maude et al. 2011).

Related Pathways

Contributors: Valerie Brown, M.D., Ph.D., Scott C. Borinstein, M.D., Ph.D., Debra Friedman, M.D.

Suggested Citation: Brown, V., S. Borinstein, D. Friedman. 2018. JAK2. My Cancer Genome https://www.padiracinnovation.org/content/disease/myeloproliferative-neoplasms/jak2/?tab=0 (Updated April 3).

Last Updated: April 3, 2018

JAK2 in Myeloproliferative Neoplasms

JAK2 is the most frequently mutated gene in MPNs. Patients diagnosed with PV, ET, and PMF carry the JAK2 V617F mutation in exon 14 at a frequency of 95%, 50–60%, and 55–65%, respectively (Baxter et al. 2005; James et al. 2005; Kralovics et al. 2005; Levine et al. 2005; Pardanani et al. 2007; Rumi et al. 2014; Scott et al. 2007). The less common JAK2 exon 12 mutation is almost exclusively seen in patients with PV and has a lower occurrence of about 3% (Pardanani et al. 2007).

Crystallography studies have shown that V617F is located within the JAK2 psueokinase domain (also known as JH2 domain), which exerts an inhibitory effect on the JH1 kinase domain (Bandaranayake et al. 2012). JAK2 V617F mutation removes this inhibitory effect, leading to constitutive activation of JAK2 (Bandaranayake et al. 2012; Shan et al. 2014; Toms et al. 2013). The activated JAK2 then acts on STAT5, a transcription factor downstream that targets multiple oncogenes leading to increased proliferation, cell-cycling, and myeloid differentiation (Da Costa Reis et al. 2009; Wernig et al. 2008). Interestingly, a JAK2 V617F mutation did not result in the development of PV in STAT5 null mice, highlighting the importance of STAT5 in disease development (Walz et al. 2012; Yan et al. 2012). JAK2 exon 12 mutations are capable of causing a stronger activation of the STAT targets as compared to the V617F mutation (Scott et al. 2007).

JAK2 figure

Figure 1. Schematic of JAK2 Protein Structure. JAK2 V617F mutation in the JH2 domain (pseudokinase domain) inhibits the JH1 domain (kinase domain), leading to the constitutive activation of JAK2. The inhibitory effect is depicted by the red arrow.

Last Updated: April 3, 2018

JAK2 c.1624_1629delAATGAA (N542_E543del) Mutation in Myeloproliferative Neoplasms

Location of mutation JH2-SH2 linker region (exon 12); Haan et al. 2010)
Frequency of JAK2 mutations in MPNs 98% in PV (Baxter et al. 2005; James et al. 2005)
50–60% in ET (Baxter et al. 2005; Kralovics et al. 2005; Levine et al. 2005)
55–65% in PMF (Baxter et al. 2005; Kralovics et al. 2005; Levine et al. 2005; Rumi et al. 2014)
Frequency of JAK2 N542_E543del mutations in JAK2-mutated MPNs ~0.9% in JAK2-mutated PV (Scott et al. 2007)
None Reported in JAK2-mutated ET
None Reported in JAK2-mutated PMF
Implications for Targeted Therapeutics
Response to JAK inhibitors Unknown at this timea

The JAK2 N542_E543del mutation results in a 6-bp inframe deletion manifesting as a deletion of the amino acids at positions 542 and 543. This mutation is seen almost exclusively in patients diagnosed with PV (Cross et al. 2005; Scott et al. 2007; Chen et al. 2014). JAK2 N542_E543del is a gain of function mutation that results in increased levels of phosphorylated JAK2 and causes a stronger activation the MAP kinase signaling pathway as compared to the JAK2 V617F mutation (Scott et al. 2007).

a The JAK1/JAK2 inhibitor ruxolitinib is FDA approved for treating PV and PMF (Harrison et al. 2012; Vannucchi et al. 2015; Verstovsek et al. 2012b). Randomized phase III trials have shown that ruxolitinib displayed a significantly improved overall survival of 69%, a 35% reduction in splenomegaly, and improved quality of life in patients diagnosed with MPN (Harrison et al. 2012; Verstovsek et al. 2012a; Verstovsek et al. 2012b). Ruxolitinib also showed clinical improvements in patients who are intolerant to hydroxyurea treatment (Pardanani et al. 2015). A phase II trial testing pacritinib was suspended due to fatal side effects (Jain et al. 2016; Komkroji et al. 2015). Other JAK2 inhibitors with potential therapeutic value are under investigation. ​

Last Updated: April 26, 2018

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