Clonal Hematopoiesis and Inflammation
Using well-defined human cohorts, numerous groups have shown that individuals with clonal hematopoiesis are more likely to develop ischemic cardiovascular disease. We now know that this association is due, at least in part, to aberrant inflammatory programs within differentiated myeloid cells carrying the clonal hematopoietic mutation. These observations have led to many investigations into disease states beyond ischemic cardiovascular disease that may be influenced by the presence of clonal hematopoiesis.
Clonal Hematopoiesis and COPD
We studied a cohort of nearly 50,000 individuals and found that clonal hematopoiesis was associated with an increased risk of having chronic obstructive pulmonary disease (COPD), a common condition and cause of death. We then showed that mice lacking Tet2 in their blood cells had worse emphysema after exposure to cigarette smoke (1).
Mice with Tet2-deleted blood cells have more emphysema after exposure to cigarette smoke and pIpC (top) or cigarette smoke alone (bottom) compared to those with Tet2 wild-type blood cells. (1)
Clonal Hematopoiesis and HLH
We found that individuals with the hyperinflammatory disease adult-onset hemophagocytic lymphohistiocytosis (HLH) are more likely to have clonal hematopoiesis. We then showed that in a mouse model of adult-onset HLH, mice with blood cells lacking Tet2 have more severe inflammatory phenotypes (2).
Three Key Questions:
1) What is the mechanistic basis for clonal hematopoiesis being associated with COPD?
2) What can the association between clonal hematopoiesis and diseases of inflammation teach us about both hematopoiesis and the pathophysiology of those diseases?
3) How can we develop meaningful therapeutic interventions to abrogate the effects of clonal hematopoiesis on diseases of inflammation?
Selected References
(1) Clonal Hematopoiesis of Indeterminate Potential and Risk of Death from COVID-19. (Pubmed)
Miller PG, Fell G, Foy B, Scherer A, Gibson CJ, Sperling AS, Burugula BB, Nakao T, Uddin MM, Warren H, Bry L, Pozdnyakova O, Frigault MJ, Bick AG, Neuberg D, Higgins JM, Mansour M, Natarajan P, Kim AS, Kitzman J, Ebert BL.
Blood. 2022. Nov 3;140(18):1993-1997.
(2) Association of Clonal Hematopoiesis with Chronic Obstructive Pulmonary Disease (Pubmed)
Miller PG*, Qiao D*, Rojas-Quintero J, Honigberg MC, Sperling AS, Gibson CJ, Bick AG, Niroula A, McConkey ME, Sandoval B, Miller BC, Shi W, Viswanathan K, Leventhal M, Werner L, Moll M, Cade BE, Barr RG, Correa A, Cupples LA, Gharib SA, Jain D, Gogarten SM, Lange LA, London SJ, Manichikul A, O’Connor GT, Oelsner EC, Redline S, Rich SS. Rotter JI, Ramachandran V, Yu B, Sholl L, Neuberg D, Jaiswal S, Levy BD, Owen CA, Natarajan P, Silverman EK, van Galen P, Tesfaigzi Y, Cho MH, Ebert BL.
Blood. 2022. Jan 20;139(3):357-368.
*Authors Contributed Equally to This Work
(3) Contribution of clonal hematopoiesis to adult-onset hemophagocytic lymphohistiocytosis (Pubmed)
Miller PG, Sperling AS, Gibson CJ, Viswanathan K, Castellano C, McConkey M, Ceremsak J, Taylor MS, Birndt S, Perner F, Arnason J, Agrawal M, Schram AM, Nikiforow S, Pihan G, Hasserjian RP, Aster JC, La Rosée P, Morgan EA, Berliner N, Ebert BL.
Blood. 2020 Dec 24;136(26):3051-3055.