Inflammatory Monocytes: Fanning the Flames of Clonal Hematopoiesis

Accumulation of somatic variants occurs naturally throughout the human lifespan and in all tissues, including the blood. While most mutations are inconsequential, some confer a competitive advantage to hematopoietic stem/progenitor cells, leading to clonal hematopoiesis (CH) –– a biological state with increased risks of atherosclerosis, thrombosis, heart failure, early mortality, and progression to frank myeloid malignancies.¹  Low-level CH is nearly universal in healthy older adults, but only in rare cases does it progress to an overt myeloid malignancy. The factors that set the scene for clinically silent clones to transform remain unclear.

In a recent report in Cancer Discovery, Dr. Anna Yeaton and colleagues demonstrate synergy between mutational and nonmutational factors in leukemogenesis. To study the trajectory of a common CH mutation, the authors generated a mouse model (Tet2^HR) with the TET2 H1881R point mutation. These mice produce normal levels of a stable but catalytic dead TET2 protein, which leads to decreased levels of methylated DNA. Although young Tet2^HR mice maintained normal hematopoiesis, 90 percent of Tet2^HR mutants developed overt myeloid neoplasms after “middle” age (14 to 24 months), ranging from “chronic” (myelodysplastic syndromes/myeloproliferative neoplasms–like) to fully “transformed” phases (acute myeloid leukemia [AML]/myeloid sarcoma). Importantly, not all cancers arising in the Tet2^HR mice harbored additional somatic mutations, suggesting that nongenetic influences induced leukemic transformation.

They next profiled the cell subtypes and transcriptional states of Tet2^HR bone marrow, comparing young and old mice to delineate the alterations in older mice with myeloid neoplasms. One of the most notable changes in the aged Tet2^HR mice was the increased percentage of monocytes, which showed enrichment of inflammatory pathways including genes required for interferon response and JAK/STAT signaling. In concordance with this, aged Tet2^HR mice with transformed disease had significantly higher levels of IL-6, IL-1B, tumor necrosis factor α, and IL-12 in the bone marrow fluid. The authors also described a distinct major histocompatibility complex (MHC) class II-high (II_hi), proinflammatory monocyte subtype in transformed Tet2^HR mice. Inflammation markers were upregulated in Tet2^HR mice with transformed disease but not in aged mice without disease, suggesting a feedback cycle in which inflammation fuels Tet2^HR hematopoietic stem and progenitor cell malignant transformation and further expands the proinflammatory MHC II^hi monocytes. To model these markers, the authors induced chronic inflammation in young mice by injecting them with lipopolysaccharide, showing that the induced expansion of MHC II^hi monocytes is in Tet2^HR, but not Tet2, wild-type mice.

To validate the significance of these findings in patients with AML, the authors stratified younger (< 60 years) and older patients by their monocytic gene signature and compared 10-year overall survival. The presence of a MHC II^hi monocyte signature correlated with significantly shorter overall survival with either TET2-mutated or de novo AML, suggesting that this signature could be a clinically useful predictor of adverse clinical outcome. Similarly, a sister publication in Nature Cancer²  defined an inflammatory gene score (iScore) and showed that it could independently predict outcomes in both adult and pediatric AML cohorts.