A new update on the biology of myelodysplastic syndromes (MDS) suggests that interventions targeting clonal cytopenia of undetermined significance (CCUS) may lead to therapies that could improve outcomes for these patients.

The update, published in Clinical Lymphoma, Myeloma, and Leukemia, notes that CCUS is a condition in which genetic mutations cause blood cell counts to drop, but it does not meet the criteria for MDS.

“The prognosis of patients with hypomethylating agent therapy failure is dismal owing to a lack of effective front- or second-line treatment options,” the authors wrote. “Thus, therapeutic strategies targeting the biological mechanisms underlying the pre-leukemic stage of MDS, CCUS, when the mutation burden is low and symptoms are minimal, can improve the dismal outcomes of these patients.”

MDS is a group of rare hematologic diseases characterized by reduced hematopoiesis in the bone marrow. MDS leads to cytopenia (low blood counts) and has the potential to progress to acute myeloid leukemia.

Read more about MDS etiology

CCUS arises in the context of pathogenic myeloid-associated genetic alterations in hematopoietic stem and progenitor cells and can lead to MDS. Currently, there is no standard treatment other than supportive care.

Researchers have studied CCUS at the cellular level, finding that mutations in specific regulatory genes such as DNMT3A and TET2 lead to differentiation of cells into persistently metabolically active myeloid cells. This process appears to be driven by the production of inflammatory cytokines including IL1b.

Furthermore, in patients with CCUS, immune cells such as natural killer cells become dysfunctional and potentially allow mutant cells to evade detection.

A better understanding of the cellular mechanisms underlying the development of CCUS will assist researchers in developing therapeutic interventions and prevention strategies to arrest the process before the disease progresses to MDS.


Colla S. EXABS-169-MDS: Update on the biology of MDS. SOHO 2023 (Society of Hematologic Oncology) 11th annual meeting, Sept. 6-7, 2023. Published online August 30, 2023.