It is well understood that only a proportion of subjects with clonal hematopoiesis ultimately develop a hematologic malignancy. To this end, several recent studies have identified genetic alterations in hematopoietic cells in the setting of clonal hematopoiesis that confer the greatest risk of eventually developing myeloid malignancies.1,2 Despite these insights, it is still clear that for most genetic alterations commonly encountered in clonal hematopoiesis, only a proportion of subjects will develop a myeloid malignancy. For example, mutations in the epigenetic regulators DNMT3A and TET2 are common in clonal hematopoiesis, but the presence of these mutations alone cannot predict for the development of acute myeloid leukemia (AML). Now, a thought-provoking study by Dr. Marlies Meisel and colleagues suggests that dissemination of bacteria from the gastrointestinal system and the ensuing microbial-dependent inflammation may be important in promoting the development of myeloid malignancy in the setting of clonal hematopoiesis.
Prior epidemiology studies have noted a connection between chronic immune stimulation from infectious diseases or autoimmue disorders with an increased risk of developing AML and myelodysplastic syndromes (MDS). For example, in population-based registries from Sweden involving approximately 9,000 patients with AML and about 42,000 matched controls, a history of any infectious disease was associated with a significantly increased risk of AML (OR, 1.3; 95% CI, 1.2-1.4).3 Additionally, prior work in mice has demonstrated that systemic dissemination of bacteria induces extramedullary hematopoiesis and emergency myelopoiesis. Based on these observations, the authors used a model system for clonal hematopoiesis (mice with deletion of Tet2 in the hematopoietic system) to study the impact of microbial infection on development of myeloid malignancies from a clonal hematopoiesis state driven by Tet2 deficiency.
It is well established that like humans, only a proportion of mice with Tet2-null hematopoietic cells develop an overt myeloid malignancy, and the factors that dictate development of myeloid malignancy in Tet2 knockout (KO) mice are not well understood. The authors identified that administration of TLR2 agonists (cell wall components of several Lactobacillus strains) induced extensive myeloproliferation in Tet2 KO mice but not littermate controls. Similarly, treatment of mice with dextran sodium sulfate (DSS), a compound known to alter intestinal barrier function, promoted myeloid malignancy development in Tet2 KO mice to a much greater extent than Tet2 wildtype littermates. In contrast, Tet2 KO mice raised in germ-free conditions failed to develop myeloproliferation even after aging to 40 weeks, which was distinct from littermate controls raised in usual specific-pathogen-free conditions. Additionally, treatment with antibiotics prevented and reversed myeloproliferation in Tet2 KO mice.
To unravel the molecular links between hematopoietic function and microbial infection, the authors analyzed the effects of microbial infection on IL-6 production in Tet2 KO mice and controls. IL-6 is a critical activator of myelopoiesis in response to systemic bacterial dissemination and can be upregulated in myeloid malignancies. Consistent with this, IL-6 was upregulated in the plasma of Tet2 KO mice and correlated with clonal expansion. IL-6 expansion was partially dependent on microbiota and could be induced by DSS or TLR2-agonist treatment. Moreover, IL-6 neutralization with an anti-IL-6 antibody could reduce myeloid disease burden in Tet2 KO mice.
In Brief
Overall, these data demonstrate that bacterial translocation and IL-6 production resulting from dysfunction of the small intestine barrier are critical for development of myeloproliferation in Tet2 null mice. Interestingly, the authors also noted that mice with Tet2 deletion in hematopoietic cells appeared to have a dysfunctional small intestine barrier and increased systemic translocation of bacteria. How mutations in hematopoietic cells could impact intestinal barrier function in this way is not clear and will likely be the subject of future work by this group. It will also be interesting to identify whether such gut dysfunction occurs in human subjects with clonal hematopoiesis. Nonetheless, from a therapeutic perspective, these findings suggest the interesting possibility that blocking inflammatory bacterial signals in subjects with clonal hematopoiesis could reduce risk of developing leukemia. Additionally, these data suggest that targeting IL-6 may be an important therapeutic approach in patients with clonal hematopoiesis and/or overt myeloid neoplasms. It would also be interesting to evaluate whether serum inflammatory cytokines may correlate with clone burden and risk of myeloid malignancy development in subjects with clonal hematopoiesis.
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Competing Interests
Dr. Abdel-Wahab indicated no relevant conflicts of interest.
