Identification of Novel Disease Alleles in Chronic Myelomonocytic Leukemias (CMML)

Patients with chronic myelomonocytic leukemia (CMML), an aggressive cancer of the blood, typically survive only two years after diagnosis. For most patients, treatments, including drug therapy and stem cell transplant, are largely ineffective. Novel, rationally designed treatment strategies are urgently needed.

CMML is a sporadic disease with no known hereditary risk. Instead, the disease arises after a patient acquires mutations in genes that control the ability of blood cells called monocytes to divide (proliferate) and mature (differentiate). In many cases, the disease-causing mutations are unknown.

Michael Deininger, MD, is leading a team to identify novel genetic factors that contribute to CMML, and to determine how these and other mutations cooperate to produce the clinical presentation. The team’s research is bolstered by a long-standing interest in the disease, during which time they have banked over 100 samples from untreated patients. In a preliminary analysis of the samples, the researchers narrowed down regions of the genome that could contain unidentified mutations responsible for CMML. They are now sequencing the candidate regions to hone in on specific genetic variations.

Paramount to the analysis, the researchers will compare genetic variations found in cancerous cells to those in non-cancerous cells. Genetic variations found in both types of cells will not undergo further analysis since they are likely inherited, and thus are not expected to contribute to the disease. Potential disease alleles will be validated in additional samples.

Genetic factors identified in this study will become targets for new therapies, and may be used as biomarkers to assess risk for acquiring CMML. Age-related mutations and chronic myelomonocytic leukemia. Mason CC, Khorashad JS, Tantravahi SK, Kelley TW, Zabriskie MS, Yan D, Pomicter AD, Reynolds KR, Eiring AM, Kronenberg Z, Sherman RL, Tyner JW, Dalley BK, Dao KH, Yandell M, Druker BJ, Gotlib J, O'Hare T, Deininger MW. Leukemia. 2016 Apr;30(4):906-13. doi: 10.1038/leu.2015.337. Epub 2015 Dec 9.


Peripheral blood smear for CMML showing abnormal cells. Chronic myelomonocytic leukemia (CMML) is an aggressive cancer of the blood that is resistant to treatment. The objective of this study is to identify acquired genetic mutations that contribute to the disease with the hope that they will become targets for new therapies.

Photo credit: Simon Calutin