Induced pluripotent stem cells (iPSCs) have emerged as powerful tools for in vitro modeling of bone marrow failure (BMF) syndromes and hereditary conditions predisposing to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). This review synthesizes recent advances in iPSC-based disease modeling for various inherited BMF/MDS disorders, including Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia syndrome, Shwachman-Diamond syndrome, and severe congenital neutropenia as well as GATA2, RUNX1, ETV6, ANKRD26, SAMD9, SAMD9L, and ADH5/ALDH2 syndromes. Although the majority of these iPSC lines are derived from patient cells, some are generated by introducing patient-specific mutations into healthy iPSC backgrounds, offering complementary approaches to disease modeling. The review highlights the ability of iPSCs to recapitulate key disease phenotypes, such as impaired hematopoietic differentiation, telomere dysfunction, and defects in DNA repair or ribosome biogenesis. We discuss how these models have enhanced our understanding of disease pathomechanisms, hematopoietic defects, and potential therapeutic approaches. Challenges in generating and maintaining disease-specific iPSCs are examined, particularly for disorders involving DNA repair. We emphasize the necessity of creating isogenic controls to elucidate genotype-phenotype relationships. Furthermore, we address limitations of current iPSC models, including genetic variability among iPSC clones derived from the same patient, and difficulties in achieving robust engraftment of iPSC-derived hematopoietic progenitor cells in mouse transplantation models. The review also explores future directions, including the potential of iPSC models for drug discovery and personalized medicine approaches. This review underscores the significance of iPSC technology in advancing our understanding of inherited hematopoietic disorders and its potential to inform novel therapeutic strategies.

Background: Sepsis is a common and serious complication in pediatric hematology oncology (PHO) patients. The Endothelial Activation and Stress Index (EASIX) score offers a potentially accessible tool for risk stratification in septic patients. Our objective was to evaluate the association of the EASIX score with adverse clinical outcomes among septic PHO patients. Methods: A retrospective review was conducted for all PHO patients admitted to the intensive care unit (ICU) with sepsis from July 2022 to December 2024. Results: A total of 53 patients with 65 sepsis events were included in this analysis. The median age was 14.9 [IQR 9.9] y and the most common disease was hematologic malignancy. In our cohort, 60% needed vasopressors, 36% required invasive mechanical ventilation, and 22% underwent renal replacement therapy (RRT). Log2-EASIX > 2.5 was associated with higher vasopressor requirements (87% versus 45% in the low log2-EASIX group, p = 0.001) and an increased need for RRT (39% versus 12%, p = 0.024). Septic PHO patients with log2-EASIX > 2.5 were 6.9 times more likely to require vasopressor support [(95% CI 1.7–27.8) p = 0.007]. In addition, PHO patients with log2-EASIX > 2.5 had a longer ICU stay (7 d versus 2 d in the low log2-EASIX group, p = 0.024) and an extended overall hospitalization (33 d versus 25 d, p = 0.029). Conclusions: A higher EASIX score was associated with adverse outcomes in critically ill septic PHO patients. Our findings suggest that the EASIX score can be used as a tool for identifying septic patients at an increased risk of clinical deterioration and poor outcomes. Prospective studies in larger cohorts are warranted to validate and expand upon these findings.

Bone marrow failure (BMF) syndromes are heterogeneous diseases characterized by impaired hematopoiesis and a risk of evolution to myelodysplastic syndrome (MDS) and leukemia. We report 6 unrelated individuals with variable BMF phenotypes and hypocellular MDS, presenting at a median age of 10 years (range, 4 weeks to 53 years). Genomic analysis revealed germ line heterozygous variants in mouse double minute 4 (MDM4), including 4 null (frameshift, nonsense, and splice site resulting in premature truncation confirmed by RNA sequencing) and 2 missense variants, of which 1 had previously been associated with a familial BMF syndrome. Mechanistically, MDM4 mutations are loss-of-function mutations leading to enhanced p53 activation. We used CRISPR/Cas9 to delete MDM4 in healthy donor hematopoietic stem and progenitor cells (HSPCs). The resulting MDM4-haploinsufficient HSPCs exhibited increased p53 activity, impaired colony-forming capacity, and reduced engraftment potential in immunodeficient mice. Complementation studies revealed both p53-binding and RING-finger domains as necessary for MDM4-mediated hematopoietic regulation. To study variant effects in a confounder-free genetic background, we introduced patient-specific MDM4 variants into induced pluripotent stem cells (iPSCs). MDM4-mutant iPSCs yielded significantly reduced erythroid and myeloid cells and exhibited increased p53 activity, as evidenced by elevated p21 expression, confirming the role of MDM4 in regulating hematopoiesis through p53. Transcriptome analysis of iPSC-derived hematopoietic cells revealed upregulation of the p53 pathway. Importantly, 1 patient with MDS acquired loss-of-function TP53 mutations, suggesting maladaptive somatic rescue. Our findings establish MDM4 deficiency as a TP53-activating syndrome, with features of BMF and variable hematopoietic manifestations. This study also highlights the critical role of the MDM4-p53 axis in maintaining hematopoietic homeostasis.

Background Sepsis is a common and serious complication in pediatric hematology oncology (PHO) patients. The Endothelial Activation and Stress Index (EASIX) score offers a potentially accessible tool for risk stratification in septic patients. Our objective was to evaluate the utility of the EASIX score in predicting adverse clinical outcomes among septic PHO patients. Methods Retrospective review of all PHO patients admitted to the intensive care unit (ICU) with sepsis from July 2022 till December 2024. Results 53 patients with 65 sepsis events were included in the analysis. The median age was 14.9 [IQR 9.9] y and the most common disease was hematologic malignancy (71%). In our cohort, 60% needed vasopressor support, 36% required IMV, and 22% underwent renal replacement therapy (RRT). Log2-EASIX >2.5 was associated with higher vasopressor requirements (87% versus 45% in the low log2-EASIX group, p=0.001), and increased need for RRT (39% versus 12%, p=0.024. PHO patients with log2-EASIX >2.5 were 6.9 more likely to require vasopressor support [(95% CI 1.7-27.8) p=0.007]. In addition, PHO patients with log2-EASIX >2.5 had longer ICU stay (7 d versus 2 d in the low log2-EASIX group, p=0.024), and extended overall hospitalization (33 d versus 25 d, p=0.029). Conclusion Higher EASIX score was associated with adverse outcomes in critically ill septic PHO patients. Our findings suggest that EASIX score can be used as a tool for identifying septic patients at increased risk of clinical deterioration and poor outcomes. Prospective studies in larger cohorts are warranted to validate and expand upon these findings.