Driver mutations in MPN

Most BCR-ABL negative MPN patients harbor one of three mutually exclusive driving mutations causing the respective disease. 60% of patients with PMF harbor the JAK2V617F mutation, approximately 30% carry a calreticulin mutation (CALR), and 8% carry a myeloproliferative leukemia virus oncogene (MPL) mutation. The mechanisms, by which these alter cell function and survival, are outlined below.

MPLW515 mut

Myeloproliferative leukaemia protein (MPL), also termed thrombopoietin receptor, is a growth factor receptor encoded by the MPL proto-oncogene. The most frequent MPL mutation in the MPN context is a G to T transversion in exon 10 [1]. The resulting MPLW515L variant of the receptor is constitutively activated, leading to aberrant JAK-STAT signalling [2].

JAK2V617F exon 14 and JAK2 exon 12 mutations

The Janus kinase 2, encoded by the JAK2 gene, is a non-receptor tyrosine kinase responsible for the phosphorylation of MPL upon ligand-induced dimerization and of STAT5 [3], thereby activating STAT signalling.

The figure above shows the functional domains of JAK2 and indicates the locus of the V617F substitution in the JH2 domain [4]. The basal kinase activity of the JH1 domain of JAK2 is autoinhibited by its JH2 domain in healthy cells [5]. In patients harboring the JAK2V617F mutation, which is defined by a G to T exchange in exon 14 of the JAK2 gene [4, 6], the interaction between JH1 and JH2 is disrupted, allowing the JH1 kinase domain to remain active [7]. This results in altered JAK-STAT signalling and is the most frequent cause for the development of a classical MPN [6]. Alternatively, mutations in exon 12 of JAK2 may be found, and these are typically associated with PV (rubra).


Calreticulin (CALR) is a chaperone for glycoproteins as well as a calcium buffer in the endoplasmic reticulum (ER) compartment of the cell. It is encoded by the CALR gene. The most frequently occurring mutations in CALR have been categorized as type I and type II mutations, wherein type I mutations are characterized by a 52 bp-deletion and type II mutations by a 5 bp-insertion in exon 9 of the CALR gene [8]. Both mutations result in a +1 bp frameshift [9] creating a common novel C-terminus that no longer includes an ER retention signal [10], allowing CALR to interact with proteins outside of the ER lumen.

The figure above displays the C-terminal amino acid sequence in CALR wildtype (CALRWT), 52 bp deletion (CALRDEL52) and 5 bp-insertion (CALRINS5) variants. It has been shown that the common C‑terminus of mutated CALR is essential for its oncogenic capability [10, 11]. Furthermore, the CALRMUT C‑terminus seems to bind the thrombopoietin receptor MPL and induce MPL homo-dimerization through mechanisms largely unknown [12], constitutively activating MPL and thereby the JAK-STAT signalling pathway [13].


The BCR-ABL oncogene is a fusion gene resulting from a reciprocal translocation between chromosome 9 and chromosome 22 (Philadelphia chromosome) first described in 1960 [14, 15].

Physiological ABL1 codes for a tyrosine kinase involved in cell proliferation, differentiation, and survival. The fusion protein lacks an N-terminal myristoylated cap, undermining autoinhibitory SH2 and SH3 docking mechanisms and rendering BCR-ABL constitutively active [16, 17].

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[2] Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006

[3] Fujitani, Y., Hibi, M., Fukada, T. et al. An alternative pathway for STAT activation that is mediated by the direct interaction between JAK and STAT. Oncogene. 1997

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[13] Majed Dasouki, Irfan Saadi, and Syed O. Ahmed. THPO-MPL pathway and bone marrow failure. Hematology/oncology and stem cell therapy. 2015

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[15] Nowell P, Hungerford D. A minute chromosome in human chronic granulocytic leukemia. Science. 1960

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[17] Nagar B, Hantschel O, Young MA, et al. Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell. 2003