Clonal hematopoiesis and hematological malignancy
William G. Dunn, … , Matthew A. McLoughlin, George S. Vassiliou
William G. Dunn, … , Matthew A. McLoughlin, George S. Vassiliou
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e180065. https://doi.org/10.1172/JCI180065.
View: Text | PDF
Review Series Article has an altmetric score of 9

Clonal hematopoiesis and hematological malignancy

Abstract

Clonal hematopoiesis (CH), the expansion of hematopoietic stem cells and their progeny driven by somatic mutations in leukemia-associated genes, is a common phenomenon that rises in prevalence with advancing age to affect most people older than 70 years. CH remains subclinical in most carriers, but, in a minority, it progresses to a myeloid neoplasm, such as acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm. Over the last decade, advances in our understanding of CH, its molecular landscape, and the risks associated with different driver gene mutations have culminated in recent developments that allow for a more precise estimation of myeloid neoplasia risk in CH carriers. In turn, this is leading to the development of translational and clinical programs to intercept and prevent CH from developing into myeloid neoplasia. Here, we give an overview of the spectrum of CH driver mutations, what is known about their pathophysiology, and how this informs the risk of incident myeloid malignancy.

Authors

William G. Dunn, Matthew A. McLoughlin, George S. Vassiliou

×

Figure 2

Malignant progression or transformation of CH.

Options: View larger image (or click on image) Download as PowerPoint
Malignant progression or transformation of CH. The transition between CH...
The transition between CH and myeloid neoplasia can occur via different routes, including direct “transformation” to de novo acute myeloid leukemia (AML) or “progression” through clonal myeloid disorders, such as clonal cytopenia of undetermined significance (CCUS), clonal monocytosis of undetermined significance (CMUS), clonal cytopenia and monocytosis of undetermined significance (CCMUS), and established myeloid neoplasms, such as the myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), and chronic myelomonocytic leukemia (CMML), or other MDS/MPN overlap syndromes, each of which has potential to progress to (secondary) AML. Dotted lines in the progression inset indicate a less frequent progression path: for example, CCUS predominantly progresses to MDS, but in a minority of cases progresses to MPN (specifically, primary myelofibrosis), while MPNs progress to AML only infrequently. Transformation from CH to AML requires additional leukemia-associated mutations, such as NPM1/FLT3-ITD mutations, whereas acquisition of additional driver mutations is not always observed at progression from CH to MDS or MPN.