Role of HMOX1 Promoter Genetic Variants in Chemoresistance and Chemotherapy Induced Neutropenia in Children with Acute Lymphoblastic Leukemia.

Whilst the survival rates of childhood acute lymphoblastic leukemia (ALL) have increased remarkably over the last decades, the therapy resistance and toxicity are still the major causes of treatment failure. It was shown that overexpression of heme oxygenase-1 (HO-1) promotes proliferation and chemoresistance of cancer cells. In humans, the HO-1 gene (HMOX1) expression is modulated by two polymorphisms in the promoter region: (GT)n-length polymorphism and single-nucleotide polymorphism (SNP) A(-413)T, with short GT repeat sequences and 413-A variants linked to an increased HO-1 inducibility. We found that the short alleles are significantly more frequent in ALL patients in comparison to the control group, and that their presence may be associated with a higher risk of treatment failure, reflecting the role of HO-1 in chemoresistance. We also observed that the presence of short alleles may predispose to develop chemotherapy-induced neutropenia. In case of SNP, the 413-T variant co-segregated with short or long alleles, while 413-A almost selectively co-segregated with long alleles, hence it is not possible to determine if SNPs are actually of phenotypic significance. Our results suggest that HO-1 can be a potential target to overcome the treatment failure in ALL patients.

Revitalizing the Aging Immune System Through Selective Stem Cell Targeting.

The interplay between aging and immune system deterioration presents a formidable challenge to human health, especially in the context of a globally aging population. Aging is associated with a decline in the body's ability to combat infections and an increased risk of various diseases, underlining the importance of rejuvenating the immune system as a strategy for promoting healthier aging. In issue 628 of Nature (2024), Ross et al. present a compelling study that introduces a novel strategy for rejuvenating the aged immune system (Ross et al., 2024). By using antibodies to selectively eliminate "aberrant" hematopoietic stem cells (HSCs), this research opens new avenues for addressing age-related immune deterioration.

Implications of stress-induced gene expression for hematopoietic stem cell aging studies.

A decline in hematopoietic stem cell (HSC) function is believed to underlie hematological shortcomings with age; however, a comprehensive molecular understanding of these changes is currently lacking. Here we provide evidence that a transcriptional signature reported in several previous studies on HSC aging is linked to stress-induced changes in gene expression rather than aging. Our findings have strong implications for the design and interpretation of HSC aging studies.

Ex vivo expansion potential of murine hematopoietic stem cells is a rare property only partially predicted by phenotype.

The scarcity of hematopoietic stem cells (HSCs) restricts their use in both clinical settings and experimental research. Here, we examined a recently developed method for expanding rigorously purified murine HSCs ex vivo. After 3 weeks of culture, only 0.1% of cells exhibited the input HSC phenotype, but these accounted for almost all functional long-term HSC activity. Input HSCs displayed varying potential for ex vivo self-renewal, with alternative outcomes revealed by single-cell multimodal RNA and ATAC sequencing profiling. While most HSC progeny offered only transient in vivo reconstitution, these cells efficiently rescued mice from lethal myeloablation. The amplification of functional HSC activity allowed for long-term multilineage engraftment in unconditioned hosts that associated with a return of HSCs to quiescence. Thereby, our findings identify several key considerations for ex vivo HSC expansion, with major implications also for assessment of normal HSC activity.

Temporal multimodal single-cell profiling of native hematopoiesis illuminates altered differentiation trajectories with age.

Aging negatively affects hematopoiesis, with consequences for immunity and acquired blood cell disorders. Although impairments in hematopoietic stem cell (HSC) function contribute to this, the in vivo dynamics of such changes remain obscure. Here, we integrate extensive longitudinal functional assessments of HSC-specific lineage tracing with single-cell transcriptome and epitope profiling. In contrast to recent suggestions from single-cell RNA sequencing alone, our data favor a defined structure of HSC/progenitor differentiation that deviates substantially from HSC-derived hematopoiesis following transplantation. Native age-dependent attrition in HSC differentiation manifests as drastically reduced lymphoid output through an early lymphoid-primed progenitor (MPP Ly-I). While in vitro activation fails to rescue lymphoid differentiation from most aged HSCs, robust lymphopoiesis can be achieved by culturing elevated numbers of candidate HSCs. Therefore, our data position rare chronologically aged HSC clones, fully competent at producing lymphoid offspring, as a prime target for approaches aimed to improve lymphopoiesis in the elderly.

A fetal tumor suppressor axis abrogates MLL-fusion-driven acute myeloid leukemia.

MLL-rearrangements (MLL-r) are recurrent genetic events in acute myeloid leukemia (AML) and frequently associate with poor prognosis. In infants, MLL-r can be sufficient to drive transformation. However, despite the prenatal origin of MLL-r in these patients, congenital leukemia is very rare with transformation usually occurring postnatally. The influence of prenatal signals on leukemogenesis, such as those mediated by the fetal-specific protein LIN28B, remains controversial. Here, using a dual-transgenic mouse model that co-expresses MLL-ENL and LIN28B, we investigate the impact of LIN28B on AML. LIN28B impedes the progression of MLL-r AML through compromised leukemia-initiating cell activity and suppression of MYB signaling. Mechanistically, LIN28B directly binds to MYBBP1A mRNA, resulting in elevated protein levels of this MYB co-repressor. Functionally, overexpression of MYBBP1A phenocopies the tumor-suppressor effects of LIN28B, while its perturbation omits it. Thereby, we propose that developmentally restricted expression of LIN28B provides a layer of protection against MYB-dependent AML.

Stem Cells, Hematopoiesis and Lineage Tracing: Transplantation-Centric Views and Beyond.

An appropriate production of mature blood cells, or hematopoiesis, is essential for organismal health and homeostasis. In this developmental cascade, hematopoietic stem cells (HSCs) differentiate into intermediate progenitor types, that subsequently give rise to the many distinct blood cell lineages. Here, we describe tools and methods that permit for temporal and native clonal-level HSC lineage tracing in the mouse, and that can now be combined with emerging single-cell molecular analyses. We integrate new insights derived from such experimental paradigms with past knowledge, which has predominantly been derived from transplantation-based approaches. Finally, we outline current knowledge and novel strategies derived from studies aimed to trace human HSC-derived hematopoiesis.

A somatic mutation in moesin drives progression into acute myeloid leukemia.

Acute myeloid leukemia (AML) arises when leukemia-initiating cells, defined by a primary genetic lesion, acquire subsequent molecular changes whose cumulative effects bypass tumor suppression. The changes that underlie AML pathogenesis not only provide insights into the biology of transformation but also reveal novel therapeutic opportunities. However, backtracking these events in transformed human AML samples is challenging, if at all possible. Here, we approached this question using a murine in vivo model with an MLL-ENL fusion protein as a primary molecular event. Upon clonal transformation, we identified and extensively verified a recurrent codon-changing mutation (Arg295Cys) in the ERM protein moesin that markedly accelerated leukemogenesis. Human cancer-associated moesin mutations at the conserved arginine-295 residue similarly enhanced MLL-ENL-driven leukemogenesis. Mechanistically, the mutation interrupted the stability of moesin and conferred a neomorphic activity to the protein, which converged on enhanced extracellular signal-regulated kinase activity. Thereby, our studies demonstrate a critical role of ERM proteins in AML, with implications also for human cancer.