Insights into the Molecular Mechanisms of Genetic Predisposition to Hematopoietic Malignancies: The Importance of Gene-Environment Interactions

Abstract

The recognition of host genetic factors underlying susceptibility to hematopoietic malignancies has increased greatly over the last decade. Historically, germline predisposition was thought to primarily affect the young. However, emerging data indicate that hematopoietic malignancies that develop in people of all ages across the human lifespan can derive from germline predisposing conditions and are not exclusively observed in younger individuals. The age at which hematopoietic malignancies manifest appears to correlate with distinct underlying biological pathways. Progression from having a deleterious germline variant to being diagnosed with overt malignancy involves complex, multistep gene-environment interactions with key external triggers, such as infection and inflammatory stimuli, driving clonal progression. Understanding the mechanisms by which predisposed clones transform under specific pressures may reveal strategies to better treat and even prevent hematopoietic malignancies from occurring.Recent unbiased genome-wide sequencing studies of children and adults with hematopoietic malignancies have revealed novel genes in which disease-causing variants are of germline origin. This paradigm shift is spearheaded by findings in myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) as well as acute lymphoblastic leukemia, but it also encompasses other cancer types. Although not without challenges, the field of genetic cancer predisposition is advancing quickly, and a better understanding of the genetic basis of hematopoietic malignancies risk affects therapeutic decisions as well as genetic counseling and testing of at-risk family members.

Figure 1.

Variation in age of HM onset for individuals with underlying genetic predisposition. Incidence of ALL (red) and AML (blue) over the lifespan. Although recent findings suggest that both ALL and AML can be triggered by an inflammatory state due to different types of environmental factors, each one also has different underlying susceptibilities, both intrinsic and extrinsic. The cartoons in the figure were created with BioRender.com (https://biorender.com).

Figure 2.

Relationship between genetic predispositions, leukemia age of onset, and secondary mutations in humans and animal models. A, Age of presentation of MDS/ AML provides clues to the underlying genetic etiology. Schematic depicting different genetic conditions predisposing to pedi­atric or adult MDS/AML and the range of ages at which they manifest. Abbreviations: FA, Fanconi anemia; SCN, severe congenital neutropenia; SDS, Shwachman–Diamond syndrome. B, Secondary acquired mutations in mouse models of B-ALL mirror those seen in human B-ALL blasts. In humans, each genetic predisposition progresses to full-blown cancer through the acquisition of specific secondary somatic mutations with common patterns often linking the initiating germline or postzygotic event and subsequent second hits. In the context of B-ALL, a proportion of mice heterozygous for Pax5 loss or expressing ETV6-RUNX1 in hematopoietic progenitors will develop leukemia when exposed to the same environmental stress. Notably, leukemic blasts acquire different patterns of mutations affecting distinct biological pathways [e.g., mutations affecting the Jak/Stat pathway in Pax5^+/− mice and mutations affecting the histone lysine demethylase (KDM) genes in mice expressing an ETV6-RUNX1 transgene]. The cartoons in the figure were created with BioRender.com (https://biorender.com) with content from Article 65272937 from stock.adobe.com.