Myeloproliferative neoplasms (MPNs) are a group of rare, malignant diseases of the bone marrow involving the production of an excess of red blood cells, white blood cells and/or platelets. MPNs are chronic diseases with only 1 to 2 new cases diagnosed per 100,000 people every year. MPNs can affect people at any age, but they are most common among adults around 60 years old. Men have a slightly higher risk to develop the disease compared to women. MPNs are caused by genetic mutations in the chromatin of the hematopoietic cells in the bone marrow. These are acquired spontaneously, due to certain genetic predispositions or as a result of environmental influences (mostly industrial mutagenic compounds). Over 80% of patients with MPNs exhibit an acquired point mutation in the gene JAK2. This so-called JAK2V617F mutation causes JAK2, a regulator of cell proliferation, to be constantly turned on. As a result, aberrant gene expression is perpetuated, the affected cell begins to divide out of control – and the illness takes its course.
If the red lineage is affects the condition is called polycytemia vera (or Vaquez disease); if platelet precursors, instead, are affected the clinical onset will be the essential thrombocytosis. MPN patients have so far been treated with ruxolitinib, a JAK2 inhibitor. Ruxolitinib (Jakavi) effectively controls the symptoms but does not offer a cure, as the malignant stem cell clone is located in the bone marrow and is generally not attacked. Discontinuing the treatment involves a high risk of relapse or progression to acute myeloid leukemia (AML). Therefore, it is of importance to discover new therapeutic approaches. That is the aim of a research team led by Veronika Sexl from Vetmeduni Vienna and Robert Kralovics from CeMM/Medical University of Vienna. Using a mouse model, they identified the CDK6 protein kinase as an important factor influencing the development of JAK2V617F-initiated MPN. They found that in the absence of CDK6, the proliferation of affected stem cells was reduced and cell death was increased.
As a consequence, the absence of CDK6 ameliorated the clinical symptoms and increased life expectancy of the sick animals. The absence of CDK6 clearly attenuates the symptoms in the long term. The spleen, greatly enlarged by the disease, shrinks back to its normal size and the progression of the disease is delayed. CDK6 promotes NFκB signaling and contributes to cytokine production while inhibiting apoptosis. The effects are not mirrored by palbociclib, a drug that blocks kinase activities of CDK4 and CDK6, showing that the functions of CDK6 in MPN pathogenesis are not related to its enzymatic function. One possible mechanism was already discovered and published in a previous research last year; i.e. CDK6 contributes to tumor formation by regulating transcriptional responses. It block the tumor suppressor p53 in hematopoietic cells. Cells lacking CDK6 kinase function are required to mutate TP53 gene to achieve a fully transformed immortalized state. CDK6 binds to the promoters of genes that antagonize p53, like Mdm4, Prmt5 and Ppm1d.
Dr. Kralovics, a senior coauthor, stated: “CDK6 is a central signaling node that connects cell cycle control; the activation of the protein NFκB, a master regulator of inflammation; apoptosis, which refers to the programmed cellular death; and malignant stem-cell function. Our work indicates that fine-tuning the level of CDK6 influences this mechanism and could potentially improve the quality of life of MPN patients. This opens up the possibility of a completely novel therapeutic approach”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Uras IZ et al., Kralovics R, Sexl V. Blood 2019 Jan 11.
Nebenfuehr S et al. Mol Cell Oncol. 2018 Sep; 5(5):e1511206.
Bellutti F et al., Sexl V. Cancer Discov. 2018 Jul; 8(7):884-897.
Scheicher R et al., Sexl V. Blood 2015 Jan 1; 125(1):90-101.
Dott. Gianfrancesco Cormaci
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