A View of Myeloid Transformation through the Hallmarks of Cancer

Abstract

The development of myeloid malignancies is influenced by a range of cell-intrinsic and cell-extrinsic factors, which can be conceptualized using the hallmarks of cancer. Although many facets of myeloid transformation are similar to those in solid tumors, there are also notable differences. Unlike solid tumors, hematologic malignancies typically exhibit fewer genetic mutations, which have been well characterized. However, understanding the cell-extrinsic factors contributing to myeloid malignancies can be challenging due to the complex interactions in the hematopoietic microenvironment. Researchers need to focus on these intricate factors to prevent the early onset of myeloid transformation and develop appropriate interventions. Significance: Myeloid malignancies are common in the elderly, and acute myeloid leukemia has an adverse prognosis in older patients. Investigating cell-extrinsic factors influencing myeloid malignancies is crucial to developing approaches for preventing or halting disease progression and predicting clinical outcomes in patients with advanced disease. Whereas successful intervention may require targeting various mechanisms, understanding the contribution of each cell-extrinsic factor will help prioritize clinical targets.

Figure 1.

Inflammation may play a role in developing myeloid malignancies from CH. In CH, inflammation can either give a competitive advantage to mutant clones or mutant clones can be more impervious to inflammation than wild-type (WT) cells. As a result, mutant cells can be more responsive to inflammatory signaling and, in turn, generate proinflammatory cytokines, thus contributing to their own selection and competitive advantage. As time passes, the increasing selection of mutant clones may lead to the development of myeloid malignancies, including MPN, MDS, and AML. As the disease advances, it perpetuates the proinflammatory BM environment and disrupts normal polyclonal hematopoiesis, eventually causing overt disease with AML blasts comprising most hematopoietic cells. Further research could help target inflammation to prevent disease progression. (Created with BioRender.com.)

Figure 2.

Differences in gut microbiota composition between healthy and AML states. In a healthy state, diverse and symbiotic gut microbiota plays a crucial role in maintaining the integrity of the intestinal epithelial barrier, interacting with parenchymal and hematopoietic cells, producing beneficial metabolites, such as butyrate, and promoting a healthy gut. However, in cases of AML, gut microbiota dysbiosis occurs, resulting in a loss of diversity, even prior to treatment. This significantly increases susceptibility to infections because pathogenic microorganisms colonize the gut. These changes can ultimately lead to increased intestinal permeability, facilitate intestinal bacterial translocation, and eventually cause bloodstream infection. Furthermore, there is a loss of butyrate production, which aids in repairing intestinal barrier damage and inhibiting LPS absorption. This imbalance can contribute to AML progression by increasing gut inflammation, the production of proinflammatory cytokines, and systemic inflammation. LPS, lipopolysaccharide. (Created with BioRender.com.)

Figure 3.

Cellular senescence can contribute to the malignant transformation of mutant clones during aging. Aging of the hematopoietic niche goes in hand with the low-grade, chronic inflammation happening during aging. With hematopoietic aging, different senescence mechanisms could be triggered and affect stromal cells within the niche, such as MSCs. Senescent cells could exacerbate the already established proinflammatory state of the aged microenvironment and accelerate the expansion of CH-mutant clones, thereby facilitating their malignant transformation. ROS, reactive oxygen species. (Created with BioRender.com.)

Figure 4.

Integrating single-cell RNA sequencing with spatial transcriptomics will be key to the understanding of the intricacies of malignant BM niches. Although numerous studies have attempted to characterize the leukemic BM microenvironment where myeloid clones evolve, most have relied solely on single-cell RNA sequencing to examine tissue-average cell composition. However, this approach falls short in the absence of spatial context, only allowing for the inference of cellular interactions at most and failing to reveal key spatial information about the microenvironment. To gain a more comprehensive understanding of the malignant BM niche in different disease states, future single-cell RNA sequencing studies must incorporate spatial transcriptomics. This approach will allow us to investigate the distribution of leukemic and nonleukemic cells, investigate the distribution of therapeutics, and identify “antileukemic” regions (i.e., areas devoid of leukemic cells). This knowledge can help devise effective niche-targeted therapies for myeloid malignancies that have been lacking. (Created with BioRender.com.)

Figure 5.

Connecting the cell-extrinsic pieces of the CH puzzle. CH refers to any state of clonal expansion in the blood system. Myeloid malignancies may result from CH. Interestingly, CH mutations are also observed in many healthy elderly individuals, with the development of blood cancer occurring only in a small subset of CH mutation carriers. This can be attributed to cell-extrinsic factors, including inflammation, microbiota, cellular senescence, and malignant/extramedullary factors. These factors are interconnected, much like puzzle pieces. For instance, microbiota dysbiosis can lead to inflammation via TLRs, which can further influence the cell composition and state of the BM niche. Additionally, cellular senescence in the niche contributes to increased inflammation, which leads to age-associated hematopoietic dysfunction. Ongoing research should investigate how these puzzle pieces connect, as well as with the presence of CH mutations and other cell-intrinsic factors or missing pieces. (Created with BioRender.com.)