Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Essential Thrombocythemia (ET) [D47.3]

OMIM numbers: 187950, 147796 (JAK2)159530 (MPL), 109091 (CALR)

Dipl.-Ing. (FH) Tanja Hinrichsen

Scientific Background

ET belongs to the group of myeloproliferative neoplasms (see MPN), which especially affect the megakaryocytic cell lineage. The disease has an incidence of 0.6-2.5:100,000 and age of diagnosis is usually between 50-60 years of age. Initially, PV, IMF, CML or other myeloproliferative neoplasms should be ruled out. One of the molecular diagnostic criteria of ET is the JAK2-V617F mutation, which leads to a dysregulation of the kinase activity and can be detected in approx. 60% of all patients suffering from ET.

In approx. 5% of all cases, the mutations W515L, K or A can be detected in the MPL gene (myeloproliferative leukemia virus oncogene), which encodes for the thrombopoietin receptor. The mutations lead to an amino acid substitution of tryptophan by leucine (W515L), lysine (W515K) or alanine (W515A) and therefore to a constitutive activation of the JAK-STAT signaling pathway. Another mutation (MPL-S505N) has been associated with familial ET. Other, less frequently occurring MPL variants (A506T, A519T, L510P) have also been described; their clinical relevance, however, is still unclear.

In approx. 50% of all cases, which don't exhibit mutations in the JAK2 or MPL gene, mutations in the CALR gene are found. They comprise different somatic deletion and insertion mutations in exon 9 that cause a frameshift and therefore lead to a specific alternative reading frame. CALR encodes a Ca2+-binding chaperone of the endoplasmic reticulum. Compared to patients with JAK2-V617F mutation or mutations in MPL, patients with CALR mutations are younger, exhibit a marked increase in platelet count, lower hemoglobin level, lower leukocyte count and lower risk of thrombosis.

Cytogenetic abnormalities can be detected at the time of diagnosis in 5-10% of all patients with ET. The observed, however not consistent abnormalities include trisomy 8, deletions in the long arm of chromosome 20 and deletions in the short arm of chromosome 9.