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

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Chronic Myelomonocytic Leukemia (CMML) [C93.30]

OMIM numbers: 607785612839 (TET2), 165360 (CBL), 612990 (ASXL1), 601573 (EZH2), 151385 (RUNX1), 164790 (NRAS), 190070 (KRAS),

Dipl.-Ing. (FH) Tanja Hinrichsen

Scientific Background

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic neoplasia with overlapping characteristics of myeloproliferative neoplasms and myelodysplastic syndromes. Therefore, CMML is clinically, morphologically and hematologically highly heterogeneous and varies from predominantly myelodysplastic to mainly myeloproliferative. The main characteristic of CMML is a persisting monocytosis > 1x109/L in the peripheral blood. Based on the number of blasts and the promonocytes in the peripheral blood and in the bone bone marrow, CMML can be categorized into 2 subgroups, CMML-1 and CMML-2. The amount of blasts (including promonocytes) is < 5% in the peripheral blood and < 10% in the bone marrow in the case of CMML-1. In the case of CMML-2, the amount of blasts (including promonocytes) is 5-19% in the peripheral blood and 10-19% in the bone marrow. Cytogenetic abnormalities are observed in 20-40% of all CMML patients; however, none of them is specific. The most frequently occurring abnormalities are trisomy 8, monosomy 7/deletion 7q as well as structural abnormalities in 12p.

Approximately 40-50% of all CMML patients show mutations in the TET2 gene. The TET2 gene is considered to be a putative tumor suppressor gene, since it is assumed to be involved in active and passive DNA demethylation processes. Besides deletions both frameshift and nonsense as well as missense mutations are found in TET2. The mutations are found in all exons, yet mainly in exon 3 and 11. CMML patients with a TET2 mutation seem to have a more favorable prognosis than patients without TET2 mutations. Approximately 20% of all CMML patients exhibit mutations in the CBL gene. The clinical relevance, however, is still unclear. Yet, TET2 and CBL mutations seem to represent an early pathogenetic event. In approximately 10% of all patients mutations are found in the RUNX1 gene and in approximately 30% in the RAS gene. Mutations in NRAS or KRAS seem to be a secondary event and have been associated with an unfavorable prognosis. Patients with mutations in the RUNX1 gene seem to be at an elevated risk of having an AML transformation; however, there is no significant statistical proof. Mutations in the ASXL1 gene and the EZH2 gene have also been associated with an unfavorable course of disease.