In JAK2 V617F-negative PMF (Primary Myelofibrosis) and ET (Essential Thrombocythemia), mutations in the juxtamembrane region of the thrombopoietin receptor MPL (Myeloproliferative leukemia virus oncogene homology) have been recently described [Pickman Y. et al, PLoS Medicine (2006) 3: 1140-1151 and Pardanani A. et al, Blood (2006) 108: 3472-3476].

MPL belongs to the hematopoietin superfamily and enables its ligand thrombopoietin (Tpo), to facilitate both global hematopoiesis and megakaryocyte growth and differenciation. The gene maps to chromosome 1q34 and contains 12 exons.

In 2006, a somatic MPL W515L mutation was described in JAK2 V617F-negative PMF [Pickman Y. et al, PLoS Medicine (2006) 3: 1140-1151].The mutation is located within exon 10 and leads to a G to T transition at nucleotide 1544 resulting in a tryptophan to leucine substitution at codon 515 of the transmembrane region.

Subsequently, a MPL W515K (TG 1543/4 to AA) was identified [Chaligne R et al, Blood (2007) 110: 3735-3743 and Vannucchi A et al, Haematologica (2008) 93: 972-976.].

MPL W515L and MPL W515K mutations were detected in about 5% and 1% of JAK2 V617F-negative PMF and ET respectively. Since then, additional MPL mutations have been reported within exon 10 of MPL [Savoia A et al, Haematologica (2007) 92: 1186-1193.].

However, only MPL515 mutations were shown to induce initiating events in PMF, mimicking the behavior of the gain of function of JAK2 V617F mutation.
Consequently, detecting MPL515 mutations in JAK2 V617F-negative sample facilitates MPN diagnostic.

See relevant publications

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