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

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Primary Myelofibrosis (PMF) [D47.4]

OMIM numbers: 254450, 612990 (ASXL1), 109091 (CALR), 301573 (EZH2), 147700 (IDH1), 147650 (IDH2), 147796 (JAK2), 159530 (MPL), 600813 (SRSF2), 612839 (TET2)

Dipl.-Ing. (FH) Tanja Hinrichsen

Scientific Background

PMF belongs to the group of myeloproliferative neoplasms (see MPN), mainly characterized by proliferation of megakaryocytes and granulocytes in the bone marrow (incidence 0.5–1.5:100,000/year, mainly occurring between 60-70 years of age). If PMF is suspected, PV, ET, CML or other myeloproliferative neoplasms should be ruled out first. The detection of the JAK2-V617F mutation, found in 50% of all PMF cases, or other clonal markers is one of the diagnostic criteria of PMF. The mutation leads to a dysregulation of kinase activity.

In approx. 1% 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. 75% 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. In PMF, CALR mutations correlate with younger age, higher platelet count and lower incidences of anemia, leukocytosis and spliceosome mutations. Patients with CALR mutations belong to the low-risk group compared to patients with mutations in the JAK2 or MPL gene or triple-negative patients.

However, if mutations in the ASXL1 gene are found the favorable prognosis of the CALR mutation turns into an unfavorable prognosis with the worst prognosis in CALR unmutated/ASXL1 mutated patients.

Generally it was shown that PMF patients with a mutation in one of the following 5 genes - ASXL1, EZH2, SRSF2, IDH1 and IDH2 - constitute a IPSS/DIPSS-plus independent high molecular risk category with a shorter overall survival and a higher risk of AML compared to patients without mutations in these genes.

Cytogenetic abnormalities can be detected at the time of diagnosis in approx. 30% of all patients. The presence of del(13)(q12q22) or der(6)t(1;6)(q21-23;p21.3) has strongly been associated with PMF, however, it is not pathognomonic for PMF. Other characteristics: deletions in the long arm of chromosome 20, partial trisomies of the long arm of chromosome 1, trisomy 8 and 9.