JAK/STAT Signalling and Haematological Malignancies


A major focus of investigation and drug screening efforts started with the discovery of JAK2V617F as a major driver of the BCR‐ABL‐negative myeloproliferative neoplasms (MPNs). An acquired somatic mutation, JAK2V617F, drives 65% of MPNs. Further studies established that these diseases almost always exhibit mutations leading to persistent JAK2‐STAT5 activation. Sequencing of the four mammalian JAKs (Janus kinases) (JAK1, JAK2, JAK3 and TYK2) and of the seven STATs (signal transducers and activators of transcriptions) in a variety of cancers identified the pathologic activation of these JAKs and STATs, by mutations in the genes themselves or in upstream or downstream regulators as significant contributors to several haematological and solid malignancies. The development of JAK2, JAK1, JAK3 and TYK2 kinase inhibitors is unfolding with JAK2, JAK1 and JAK3 inhibitors being approved in certain conditions. Altogether, the JAK/STAT pathway became a new gold mine for discovery and therapy in haematological cancers.

Key Concepts

  • The JAK/STAT pathway has a central role in cytokine signalling in normal haematopoiesis.
  • The JAK/STAT pathway is frequently pathologically activated by several mechanisms in many types of haematological malignancies.
  • The JAK/STAT pathway can be targeted by small molecules.
  • The JAK/STAT pathway can be pathologically activated by down‐modulation of negative regulators such as phosphatases.
  • Constitutive STAT activation in blood cancers can be the result of several activated kinases, not only JAKs.
  • JAK2 activation is the main mechanismresponsible of the poorprognosis of mostpediatric B‐cell acute lymphoblasticleukemia.

Keywords: JAK/STAT; signalling; leukaemia; lymphoma; myeloproliferative neoplasms; myelodysplastic syndromes; JAK inhibitors; STAT inhibitors

Figure 1. The cytokine receptor superfamily. Cytokine receptor family consists of type I and type II subfamilies, based on homologies in the sequences of the extracellular domains. Each subfamily is divided on classes based on the homo‐ or heterodimerisation mechanism of activation and on the types of chains assembled. The precise JAKs among the four JAKs (JAK1, JAK2, TYK2, JAK3) utilised by each class of receptors are indicated.
Figure 2. Oncogenic somatic mutations in JAK2 and MPL/TpoR in myeloproliferative neoplasms. (a) Upper. The pseudokinase domain V617F mutation activates the kinase domain. Rare activating mutations occur in the SH2‐JH2 linker in Polycythemia Vera (exon 12 mutations). Bottom. A model of JAK2 showing the N‐terminal FERM domain binding to a cytokine receptor cytosolic domain. (b) Activating mutations in the cytosolic juxtamembrane domain of TpoR.
Figure 3. Domain structure of STAT proteins and STAT3 oncogenic mutants.
Figure 4. Domain structure of calreticulin and mutants in exon 9 that are prevalent in myeloproliferative neoplasms. Upper. Structure of calreticulin and function of each domain. Bottom. Exon 9 deletions and insertions lead to an identical frameshift that changes a negatively charged sequence and the KDEL ER retention motif to a positively charged sequence.


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Further Reading

Cazzola M and Kralovics R (2014) From Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms. Blood 123 (24): 3714–3719.

Constantinescu SN, Leroy E, Gryshkova V, et al. (2013) Activating Janus kinase pseudokinase domain mutations in myeloproliferative and other blood cancers. Biochemical Society Transactions 41 (4): 1048–1054.

Daver N, Cortes J, Newberry K, et al. (2015) Ruxolitinib in combination with Lenalidomide as therapy for patients with myelofibrosis. Haematologica 100: 1058–1063. pii: haematol.2015.126821.

Degryse S, de Bock CE, Cox L, et al. (2014) JAK3 mutants transform hematopoietic cells through JAK1 activation, causing T‐cell acute lymphoblastic leukemia in a mouse model. Blood 124 (20): 3092–3100.

Hammarén HM, Ungureanu D, Grisouard J, et al. (2015) ATP binding to the pseudokinase domain of JAK2 is critical for pathogenic activation. Proceedings of the National Academy of Sciences U S A 112 (15): 4642–4647.

Hornakova T, Springuel L, Devreux J, et al. (2011) Oncogenic JAK1 and JAK2‐activating mutations resistant to ATP‐competitive inhibitors. Haematologica 96 (6): 845–853.

Lundberg P, Nienhold R, Ambrosetti A, et al. (2014) Somatic mutations in calreticulin can be found in pedigrees with familial predisposition to myeloproliferative neoplasms. Blood 123 (17): 2744–2745.

O'Shea JJ, Schwartz DM, Villarino AV, et al. (2015) The JAK‐STAT pathway: impact on human disease and therapeutic intervention. Annual Review of Medicine 66: 311–328.

Shochat C, Tal N, Gryshkova V, et al. (2014) Novel activating mutations lacking cysteine in type I cytokine receptors in acute lymphoblastic leukemia. Blood 124 (1): 106–110.

Vannucchi AM, Kantarjian HM, Kiladjian JJ, et al. (2015) A pooled analysis of overall survival in COMFORT‐I and COMFORT‐II, 2 randomized phase 3 trials of ruxolitinib for the treatment of myelofibrosis. Haematologica PMID:26069290.

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Constantinescu, Stefan N, and Vainchenker, William(Oct 2015) JAK/STAT Signalling and Haematological Malignancies. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024988]