• What is JAK2?
  • JAK2 in Myeloproliferative Neoplasms
  • Clinical Trials

JAK2

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

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