Juvenile myelomonocytic leukemia (JMML) is a rare pediatric leukemia characterized by mutations in five canonical RAS pathway genes. The diagnosis is made by typical clinical and hematological findings associated with a compatible mutation. Although this is sufficient for clinical decision-making in most JMML cases, more in-depth analysis can include DNA methylation class and panel sequencing analysis for secondary mutations. NRAS-initiated JMML is heterogeneous and adequate management ranges from watchful waiting to allogeneic hematopoietic stem cell transplantation (HSCT). Upfront azacitidine in KRAS patients can achieve long-term remissions without HSCT; if HSCT is required, a less toxic preparative regimen is recommended. Germline CBL patients often experience spontaneous resolution of the leukemia or exhibit stable mixed chimerism after HSCT. JMML driven by PTPN11 or NF1 is often rapidly progressive, requires swift HSCT and may benefit from pretransplant therapy with azacitidine. Because graft-versus-leukemia alloimmunity is central to cure high risk patients, the immunosuppressive regimen should be discontinued early after HSCT.

PEG asparaginase is an important and established drug in the treatment of pediatric acute lymphoblastic leukemia (ALL). Severe hypertriglyceridemia is a rare complication of PEG asparaginase in combination with glucocorticoids. We report a case of excessive hypertriglyceridemia in a child during ALL induction therapy successfully treated by lipid apheresis and give a literature review on the management of hypertriglyceridemia in children treated for ALL.

PURPOSE: Clonal hematopoiesis (CH) has been associated with a variety of adverse outcomes, most notably hematologic malignancy and ischemic cardiovascular disease. A series of recent studies also suggest that CH may play a role in the outcomes of patients with solid tumors, including breast cancer. Here, we review the clinical and biological data that underlie potential connections between CH, inflammation, and breast cancer, with a focus on the prevalence and impact of clonal hematopoiesis of indeterminate potential in patients with breast cancer. METHODS: We summarize data from multiple studies, including a series of cohorts of patients with breast cancer, to assess the prevalence of CH, the relationship between CH and exposure to cytotoxic therapy, and the correlation between CH and breast cancer–specific outcomes. RESULTS: Our findings indicate that CH is prevalent among patients with breast cancer, particularly those treated with cytotoxic therapies. However, there are no definitive data to support an association between the presence of CH and breast cancer–specific outcomes. CONCLUSION: Current data do not support routine CH testing in patients with breast cancer, nor should the presence of CH influence decisions regarding breast cancer therapy in most patients. However, larger, long-term studies are necessary to further define the implications of CH in patients with breast cancer and guide clinical decision making.

Iron is an essential element for most cellular processes, and recent evidence highlighted its role in regulating the function of hematopoietic stem cells (HSCs). Abnormal iron levels affect HSC quiescence and self-renewal; however, the mechanism by which iron overload (IO) influences HSC function is still unknown. Here, we show that intracellular IO impairs mitochondrial fitness and bioenergetics, inducing metabolic rewiring. In thalassemic mice, as a model of chronic IO, HSCs accumulate elevated mitochondrial reactive oxygen species (mtROS), low mitochondrial membrane potential, and reduced oxidative phosphorylation. Mitochondrial defects are confirmed in 2 other models of IO, sickle cell disease and iron-loaded wild-type mice, and in vivo iron reduction rescues HSC mitochondria. IO HSCs are highly proliferating and, in the presence of damaged mitochondria, rely on glycolysis for energy production. Notably, restoration of mitochondrial function by targeting in vivo mtROS improved the quiescence and self-renewal of IO HSCs. Our results unravel the critical interplay between iron, ROS, and mitochondrial activity in HSCs, revealing that IO shapes HSC metabolic programs.

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