Clinical and Genomic-Based Decision Support System to Define the Optimal Timing of Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Myelodysplastic Syndromes.

PURPOSE: Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only potentially curative treatment for patients with myelodysplastic syndromes (MDS). Several issues must be considered when evaluating the benefits and risks of HSCT for patients with MDS, with the timing of transplantation being a crucial question. Here, we aimed to develop and validate a decision support system to define the optimal timing of HSCT for patients with MDS on the basis of clinical and genomic information as provided by the Molecular International Prognostic Scoring System (IPSS-M). PATIENTS AND METHODS: We studied a retrospective population of 7,118 patients, stratified into training and validation cohorts. A decision strategy was built to estimate the average survival over an 8-year time horizon (restricted mean survival time [RMST]) for each combination of clinical and genomic covariates and to determine the optimal transplantation policy by comparing different strategies. RESULTS: Under an IPSS-M based policy, patients with either low and moderate-low risk benefited from a delayed transplantation policy, whereas in those belonging to moderately high-, high- and very high-risk categories, immediate transplantation was associated with a prolonged life expectancy (RMST). Modeling decision analysis on IPSS-M versus conventional Revised IPSS (IPSS-R) changed the transplantation policy in a significant proportion of patients (15% of patient candidate to be immediately transplanted under an IPSS-R-based policy would benefit from a delayed strategy by IPSS-M, whereas 19% of candidates to delayed transplantation by IPSS-R would benefit from immediate HSCT by IPSS-M), resulting in a significant gain-in-life expectancy under an IPSS-M-based policy (P = .001). CONCLUSION: These results provide evidence for the clinical relevance of including genomic features into the transplantation decision making process, allowing personalizing the hazards and effectiveness of HSCT in patients with MDS.

Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes.

Mutations in UBA1, which are disease-defining for VEXAS syndrome, have been reported in patients diagnosed with myelodysplastic syndromes (MDS). Here, we define the prevalence and clinical associations of UBA1 mutations in a representative cohort of patients with MDS. Digital droplet PCR profiling of a selected cohort of 375 male patients lacking MDS disease-defining mutations or established WHO disease classification identified 28 patients (7%) with UBA1 p.M41T/V/L mutations. Using targeted sequencing of UBA1 in a representative MDS cohort (n=2,027), we identified an additional 27 variants in 26 patients (1%), which we classified as likely/pathogenic (n=12) and unknown significance (n=15). Among the total 40 patients with likely/pathogenic variants (2%), all were male and 63% were classified by WHO2016 as MDS-MLD/SLD. Patients had a median of one additional myeloid gene mutation, often in TET2 (n=12), DNMT3A (n=10), ASXL1 (n=3), or SF3B1 (n=3). Retrospective clinical review where possible showed that 83% (28/34) UBA1-mutant cases had VEXAS-associated diagnoses or inflammatory clinical presentation. The prevalence of UBA1-mutations in MDS patients argues for systematic screening for UBA1 in the management of MDS.

DNA methylation profiling of myelodysplastic syndromes and clinical response to azacitidine: A multicentre retrospective study.

Real-world data have revealed that a substantial portion of patients with myelodysplastic syndromes (MDS) does not respond to epigenetic therapy with hypomethylating agents (HMAs). The cellular and molecular reasons for this resistance to the demethylating agent and biomarkers that would be able to predict the treatment refractoriness are largely unknown. In this study, we shed light on this enigma by characterizing the epigenomic profiles of patients with MDS treated with azacitidine. Our approach provides a comprehensive view of the evolving DNA methylation architecture of the disease and holds great potential for advancing our understanding of MDS treatment responses to HMAs.

Single-cell Multiomics Analysis of Myelodysplastic Syndromes and Clinical Response to Hypomethylating Therapy.

Alterations in epigenetic marks, such as DNA methylation, represent a hallmark of cancer that has been successfully exploited for therapy in myeloid malignancies. Hypomethylating agents (HMA), such as azacitidine, have become standard-of-care therapy to treat myelodysplastic syndromes (MDS), myeloid neoplasms that can evolve into acute myeloid leukemia. However, our capacity to identify who will respond to HMAs, and the duration of response, remains limited. To shed light on this question, we have leveraged the unprecedented analytic power of single-cell technologies to simultaneously map the genome and immunoproteome of MDS samples throughout clinical evolution. We were able to chart the architecture and evolution of molecular clones in precious paired bone marrow MDS samples at diagnosis and posttreatment to show that a combined imbalance of specific cell lineages with diverse mutational profiles is associated with the clinical response of patients with MDS to hypomethylating therapy. SIGNIFICANCE: MDS are myeloid clonal hemopathies with a low 5-year survival rate, and approximately half of the cases do not respond to standard HMA therapy. Our innovative single-cell multiomics approach offers valuable biological insights and potential biomarkers associated with the demethylating agent efficacy. It also identifies vulnerabilities that can be targeted using personalized combinations of small drugs and antibodies.

Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo.

Multiple myeloma is the second most common hematological malignancy in adults and remains an incurable disease. B cell maturation antigen (BCMA)-directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval. However, despite promising results, most patients eventually become refractory and relapse, highlighting the need for alternative strategies. Engineered T cells secreting TCE antibodies (STAb) represent a promising strategy that combines the advantages of adoptive cell therapies and bispecific antibodies. Here, we undertook a comprehensive preclinical study comparing the therapeutic potential of T cells either expressing second-generation anti-BCMA CARs (CAR-T) or secreting BCMAxCD3 TCEs (STAb-T) in a T cell-limiting experimental setting mimicking the conditions found in patients with relapsed/refractory multiple myeloma. STAb-T cells recruited T cell activity at extremely low effector-to-target ratios and were resistant to inhibition mediated by soluble BCMA released from the cell surface, resulting in enhanced cytotoxic responses and prevention of immune escape of multiple myeloma cells in vitro. These advantages led to robust expansion and persistence of STAb-T cells in vivo, generating long-lived memory BCMA-specific responses that could control multiple myeloma progression in xenograft models, outperforming traditional CAR-T cells. These promising preclinical results encourage clinical testing of the BCMA-STAb-T cell approach in relapsed/refractory multiple myeloma.

Persistence of Chronic Lymphocytic Leukemia Stem-like Populations under Simultaneous In Vitro Treatment with Curcumin, Fludarabine, and Ibrutinib: Implications for Therapy Resistance.

Leukemic stem cells (LSCs) possess similar characteristics to normal hematopoietic stem cells, including self-renewal capacity, quiescence, ability to initiate leukemia, and drug resistance. These cells play a significant role in leukemia relapse, persisting even after apparent remission. LSCs were first described in 1994 by Lapidot et al. Although they have been extensively studied in acute leukemia, more LSC research is still needed in chronic lymphocytic leukemia (CLL) to understand if reduced apoptosis in mature cells should still be considered as the major cause of this disease. Here, we provide new evidence suggesting the existence of stem-like cell populations in CLL, which may help to understand the disease as well as to develop effective treatments. In this study, we identified a potential leukemic stem cell subpopulation using the tetraploid CLL cell line I83. This subpopulation is characterized by diploid cells that were capable of generating the I83 tetraploid population. Furthermore, we adapted a novel flow cytometry analysis protocol to detect CLL subpopulations with stem cell properties in peripheral blood samples and primary cultures from CLL patients. These cells were identified by their co-expression of CD19 and CD5, characteristic markers of CLL cells. As previously described, increased alkaline phosphatase (ALP) activity is indicative of stemness and pluripotency. Moreover, we used this method to investigate the potential synergistic effect of curcumin in combination with fludarabine and ibrutinib to deplete this subpopulation. Our results confirmed the effectiveness of this ALP-based analysis protocol in detecting and monitoring leukemic stem-like cells in CLL. This analysis also identified limitations in eradicating these populations using in vitro testing. Furthermore, our findings demonstrated that curcumin significantly enhanced the effects of fludarabine and ibrutinib on the leukemic fraction, exhibiting synergistic effects (combination drug index, CDI 0.97 and 0.37, respectively). Our results lend support to the existence of potential stem-like populations in CLL cell lines, and to the idea that curcumin could serve as an effective adjuvant in therapies aimed at eliminating these populations and improving treatment efficacy.

A framework for the clinical implementation of optical genome mapping in hematologic malignancies.

Optical Genome Mapping (OGM) is rapidly emerging as an exciting cytogenomic technology both for research and clinical purposes. In the last 2 years alone, multiple studies have demonstrated that OGM not only matches the diagnostic scope of conventional standard of care cytogenomic clinical testing but it also adds significant new information in certain cases. Since OGM consolidates the diagnostic benefits of multiple costly and laborious tests (e.g., karyotyping, fluorescence in situ hybridization, and chromosomal microarrays) in a single cost-effective assay, many clinical laboratories have started to consider utilizing OGM. In 2021, an international working group of early adopters of OGM who are experienced with routine clinical cytogenomic testing in patients with hematological neoplasms formed a consortium (International Consortium for OGM in Hematologic Malignancies, henceforth "the Consortium") to create a consensus framework for implementation of OGM in a clinical setting. The focus of the Consortium is to provide guidance for laboratories implementing OGM in three specific areas: validation, quality control and analysis and interpretation of variants. Since OGM is a complex technology with many variables, we felt that by consolidating our collective experience, we could provide a practical and useful tool for uniform implementation of OGM in hematologic malignancies with the ultimate goal of achieving globally accepted standards.

Two-Time Multiplexed Targeted Next-Generation Sequencing Might Help the Implementation of Germline Screening Tools for Myelodysplastic Syndromes/Hematologic Neoplasms.

Next-generation sequencing (NGS) tools have importantly helped the classification of myelodysplastic syndromes (MDS), guiding the management of patients. However, new concerns are under debate regarding their implementation in routine clinical practice for the identification of germline predisposition. Cost-effective targeted NGS tools would improve the current standardized studies and genetic counseling. Here, we present our experience in a preliminary study detecting variants using a two-time multiplexed library strategy. Samples from different MDS patients were first mixed before library preparation and later multiplexed for a sequencing run. Two different mixes including a pool of three (3×) and four (4×) samples were evaluated. The filtered variants found in the individually sequenced samples were compared with the variants found in the two-time multiplexed studies to determine the detection efficiency scores. The same candidate variants were found in the two-time multiplexed studies in comparison with the individual tNGS. The variant allele frequency (VAF) values of the candidate variants were also compared. No significant differences were found between the expected and observed VAF percentages in both the 3× (p-value 0.74) and 4× (p-value 0.34) multiplexed studies. Our preliminary results suggest that the two-time multiplexing strategy might have the potential to help reduce the cost of evaluating germline predisposition.

Effect of mixing at weaning and nutrient density of the weaner diet on growth performance and welfare of pigs to slaughter.

BACKGROUND: Mixing pigs at weaning can compromise pig welfare and growth. Therefore, grouping littermates together may allow a diet nutrient and energy density reduction during the nursery period to reduce feed cost without affecting slaughter weight. This study investigated the combined effect of mixing and reducing dietary energy and nutrient density on growth performance, body lesions (BL), and behaviour in pigs from weaning to slaughter. RESULTS: Forty-eight litters [554 pigs, 11-12 pigs/litter; Danish Duroc × (Large White × Landrace)] were included in the trial. At 28 days of age, pigs were weaned and housed in nursery rooms in litter groups (INTACT, n = 24) or mixed with other litters and grouped by weight to reduce within-pen pig weight variation (MIXED, n = 24). A dietary regimen meeting pigs' nutritional requirements (CON) and a low-density dietary regimen (LOW; -10% energy and protein) completed a 2 × 2 factorial arrangement (Mixing x Diet, n = 12). On day 74 of age, pigs moved to the grower-finisher accommodation without further mixing and all pigs received the CON dietary regimen. Mixing increased FCR by 4.0% during the nursery period (p = 0.003). Nursery pigs fed LOW experienced a growth retardation which was maintained until slaughter (-2.6 kg slaughter weight; p = 0.025). Initial differences in the coefficient of variation (CV) between MIXED (10.4%) and INTACT (17.6%; p < 0.001) pigs were reduced in CON pens but not in LOW pens (interaction p = 0.025) at the end of the nursery period. MIXED pigs had more fights and BL (p < 0.001) at weaning and showed more aggression (p = 0.003) after being moved to the grower-finisher rooms. At the end of the nursery period, MIXED pigs fed LOW showed the highest number of aggressive behaviours around the feeder (interaction; p = 0.003) and pigs fed LOW showed more damaging behaviour (p < 0.001). CONCLUSIONS: Mixing animals at weaning had limited impact on growth performance but impaired welfare which was aggravated by energy and nutrient reduction in the nursery diet. Decreasing dietary nutrient density in the nursery stage retarded growth, which could not be compensated for during the growing-finishing period.

Mutational Profile Enables the Identification of a High-Risk Subgroup in Myelodysplastic Syndromes with Isolated Trisomy 8.

Trisomy 8 (+8) is the most frequent trisomy in myelodysplastic syndromes (MDS) and is associated with clinical heterogeneity and intermediate cytogenetic risk when found in isolation. The presence of gene mutations in this group of patients and the prognostic significance has not been extensively analyzed. Targeted deep sequencing was performed in a cohort of 79 MDS patients showing isolated +8. The most frequently mutated genes were: TET2 (38%), STAG2 (34.2%), SRSF2 (29.1%) and RUNX1 (26.6%). The mutational profile identified a high-risk subgroup with mutations in STAG2, SRSF2 and/or RUNX1, resulting in shorter time to acute myeloid leukemia progression (14 months while not reached in patients without these mutations, p < 0.0001) and shorter overall survival (23.7 vs. 46.3 months, p = 0.001). Multivariate analyses revealed the presence of mutations in these genes as an independent prognostic factor in MDS showing +8 isolated (HR: 3.1; p < 0.01). Moreover, 39.5% and 15.4% of patients classified as low/intermediate risk by the IPSS-R and IPSS-M, respectively, were re-stratified as a high-risk subgroup based on the mutational status of STAG2, SRSF2 and RUNX1. Results were validated in an external cohort (n = 2494). In summary, this study validates the prognosis significance of somatic mutations shown in IPSS-M and adds STAG2 as an important mutated gene to consider in this specific subgroup of patients. The mutational profile in isolated +8 MDS patients could, therefore, offer new insights for the correct management of patients with a higher risk of leukemic transformation.

Regions of homozygosity confer a worse prognostic impact in myelodysplastic syndrome with normal karyotype.

Half of the myelodysplastic syndromes (MDS) have normal karyotype by conventional banding analysis. The percentage of true normal karyotype cases can be reduced by 20-30% with the complementary application of genomic microarrays. We here present a multicenter collaborative study of 163 MDS cases with a normal karyotype (≥10 metaphases) at diagnosis. All cases were analyzed with the ThermoFisher® microarray (either SNP 6.0 or CytoScan HD) for the identification of both copy number alteration(CNA) and regions of homozygosity (ROH). Our series supports that 25 Mb cut-off as having the most prognostic impact, even after adjustment by IPSS-R. This study highlights the importance of microarrays in MDS patients, to detect CNAs and especially to detect acquired ROH which has demonstrated a high prognostic impact.

Real-World Validation of Molecular International Prognostic Scoring System for Myelodysplastic Syndromes.

PURPOSE: Myelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms in which a risk-adapted treatment strategy is needed. Recently, a new clinical-molecular prognostic model, the Molecular International Prognostic Scoring System (IPSS-M) was proposed to improve the prediction of clinical outcome of the currently available tool (Revised International Prognostic Scoring System [IPSS-R]). We aimed to provide an extensive validation of IPSS-M. METHODS: A total of 2,876 patients with primary MDS from the GenoMed4All consortium were retrospectively analyzed. RESULTS: IPSS-M improved prognostic discrimination across all clinical end points with respect to IPSS-R (concordance was 0.81 v 0.74 for overall survival and 0.89 v 0.76 for leukemia-free survival, respectively). This was true even in those patients without detectable gene mutations. Compared with the IPSS-R based stratification, the IPSS-M risk group changed in 46% of patients (23.6% and 22.4% of subjects were upstaged and downstaged, respectively).In patients treated with hematopoietic stem cell transplantation (HSCT), IPSS-M significantly improved the prediction of the risk of disease relapse and the probability of post-transplantation survival versus IPSS-R (concordance was 0.76 v 0.60 for overall survival and 0.89 v 0.70 for probability of relapse, respectively). In high-risk patients treated with hypomethylating agents (HMA), IPSS-M failed to stratify individual probability of response; response duration and probability of survival were inversely related to IPSS-M risk.Finally, we tested the accuracy in predicting IPSS-M when molecular information was missed and we defined a minimum set of 15 relevant genes associated with high performance of the score. CONCLUSION: IPSS-M improves MDS prognostication and might result in a more effective selection of candidates to HSCT. Additional factors other than gene mutations can be involved in determining HMA sensitivity. The definition of a minimum set of relevant genes may facilitate the clinical implementation of the score.

The Secondary Myelodysplastic Neoplasms (MDS) Jigsaw.

There is a great deal of controversy in the hematologic community regarding the classification of secondary myelodysplastic neoplasms (MDSs). Current classifications are based on the presence of genetic predisposition and MDS post-cytotoxic therapy (MDS-pCT) etiologies. However, since these risk factors are not exclusive for secondary MDSs and there are multiple overlapping scenarios, a comprehensive and definitive classification is yet to come. In addition, a sporadic MDS might arise after a primary tumor fulfills the diagnostic criteria of MDS-pCT without a causative cytotoxicity. In this review, we describe the triggering pieces of a secondary MDS jigsaw: previous cytotoxic therapy, germline predisposition and clonal hematopoiesis. Epidemiological and translational efforts are needed to put these pieces together and ascertain the real weight of each of these pieces in each MDS patient. Future classifications must contribute to understanding the role of secondary MDS jigsaw pieces in different concomitant or independent clinical scenarios associated with the primary tumor.

European standard clinical practice - Key issues for the medical care of individuals with familial leukemia.

Although hematologic malignancies (HM) are no longer considered exclusively sporadic, additional awareness of familial cases has yet to be created. Individuals carrying a (likely) pathogenic germline variant (e.g., in ETV6, GATA2, SAMD9, SAMD9L, or RUNX1) are at an increased risk for developing HM. Given the clinical and psychological impact associated with the diagnosis of a genetic predisposition to HM, it is of utmost importance to provide high-quality, standardized patient care. To address these issues and harmonize care across Europe, the Familial Leukemia Subnetwork within the ERN PaedCan has been assigned to draft an European Standard Clinical Practice (ESCP) document reflecting current best practices for pediatric patients and (healthy) relatives with (suspected) familial leukemia. The group was supported by members of the German network for rare diseases MyPred, of the Host Genome Working Group of SIOPE, and of the COST action LEGEND. The ESCP on familial leukemia is proposed by an interdisciplinary team of experts including hematologists, oncologists, and human geneticists. It is intended to provide general recommendations in areas where disease-specific recommendations do not yet exist. Here, we describe key issues for the medical care of familial leukemia that shall pave the way for a future consensus guideline: (i) identification of individuals with or suggestive of familial leukemia, (ii) genetic analysis and variant interpretation, (iii) genetic counseling and patient education, and (iv) surveillance and (psychological) support. To address the question on how to proceed with individuals suggestive of or at risk of familial leukemia, we developed an algorithm covering four different, partially linked clinical scenarios, and additionally a decision tree to guide clinicians in their considerations regarding familial leukemia in minors with HM. Our recommendations cover, not only patients but also relatives that both should have access to adequate medical care. We illustrate the importance of natural history studies and the need for respective registries for future evidence-based recommendations that shall be updated as new evidence-based standards are established.

Myelodysplastic Syndromes with Isolated del(5q): Value of Molecular Alterations for Diagnostic and Prognostic Assessment.

Myelodysplastic syndromes (MDS) are a group of clonal hematological neoplasms characterized by ineffective hematopoiesis in one or more bone marrow cell lineages. Consequently, patients present with variable degrees of cytopenia and dysplasia. These characteristics constitute the basis for the World Health Organization (WHO) classification criteria of MDS, among other parameters, for the current prognostic scoring system. Although nearly half of newly diagnosed patients present a cytogenetic alteration, and almost 90% of them harbor at least one somatic mutation, MDS with isolated del(5q) constitutes the only subtype clearly defined by a cytogenetic alteration. The results of several clinical studies and the advances of new technologies have allowed a better understanding of the biological basis of this disease. Therefore, since the first report of the "5q- syndrome" in 1974, changes and refinements have been made in the definition and the characteristics of the patients with MDS and del(5q). Moreover, specific genetic alterations have been found to be associated with the prognosis and response to treatments. The aim of this review is to summarize the current knowledge of the molecular background of MDS with isolated del(5q), focusing on the clinical and prognostic relevance of cytogenetic alterations and somatic mutations.

Fecal Microbiota and Hair Glucocorticoid Concentration Show Associations with Growth during Early Life in a Pig Model.

Identifying characteristics associated with fast or slow growth during early life in a pig model will help in the design of nutritional strategies or recommendations during infancy. The aim of this study was to identify if a differential growth during lactation and/or the nursery period may be associated with fecal microbiota composition and fermentation capacity, as well as to leave a print of glucocorticoid biomarkers in the hair. Seventy-five commercial male and female pigs showing extreme growth in the lactation and nursery periods were selected, creating four groups (First, lactation growth, d0−d21; second, nursery growth, d21−d62): Slow_Slow, Slow_Fast, Fast_Slow, and Fast_Fast. At d63 of life, hair and fecal samples were collected. Fast-growing pigs during nursery had higher cortisone concentrations in the hair (p < 0.05) and a tendency to have a lower cortisol-to-cortisone ratio (p = 0.061). Both lactation and nursery growth conditioned the fecal microbiota structure (p < 0.05). Additionally, fast-growing pigs during nursery had higher evenness (p < 0.05). Lactation growth influenced the relative abundance of eight bacterial genera, while nursery growth affected only two bacterial genera (p < 0.05). The fecal butyrate concentration was higher with fast growth in lactation and/or nursery (p < 0.05), suggesting it has an important role in growth, while total SCFA and acetate were related to lactation growth (p < 0.05). In conclusion, piglets' growth during nursery and, especially, the lactation period was associated with changes in their microbiota composition and fermentation capacity, evidencing the critical role of early colonization on the establishment of the adult microbiota. Additionally, cortisol conversion to cortisone was increased in animals with fast growth, but further research is necessary to determine its implications.

Genomic profiling for clinical decision making in myeloid neoplasms and acute leukemia.

Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. Although assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the past several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole-exome sequencing, whole-genome sequencing, and whole-transcriptome sequencing or RNA sequencing. In patients with myeloid neoplasms, whole-genome sequencing represents a potential replacement for both conventional cytogenetic and sequencing approaches, providing rapid and accurate comprehensive genomic profiling. DNA sequencing methods are used not only for detecting somatically acquired gene mutations but also for identifying germline gene mutations associated with inherited predisposition to hematologic neoplasms. The 2022 International Consensus Classification of myeloid neoplasms and acute leukemias makes extensive use of genomic data. The aim of this report is to help physicians and laboratorians implement genomic testing for diagnosis, risk stratification, and clinical decision making and illustrates the potential of genomic profiling for enabling personalized medicine in patients with hematologic neoplasms.

Targeting the EIF2AK1 Signaling Pathway Rescues Red Blood Cell Production in SF3B1-Mutant Myelodysplastic Syndromes With Ringed Sideroblasts.

SF3B1 mutations, which occur in 20% of patients with myelodysplastic syndromes (MDS), are the hallmarks of a specific MDS subtype, MDS with ringed sideroblasts (MDS-RS), which is characterized by the accumulation of erythroid precursors in the bone marrow and primarily affects the elderly population. Here, using single-cell technologies and functional validation studies of primary SF3B1-mutant MDS-RS samples, we show that SF3B1 mutations lead to the activation of the EIF2AK1 pathway in response to heme deficiency and that targeting this pathway rescues aberrant erythroid differentiation and enables the red blood cell maturation of MDS-RS erythroblasts. These data support the development of EIF2AK1 inhibitors to overcome transfusion dependency in patients with SF3B1-mutant MDS-RS with impaired red blood cell production. SIGNIFICANCE: MDS-RS are characterized by significant anemia. Patients with MDS-RS die from a shortage of red blood cells and the side effects of iron overload due to their constant need for transfusions. Our study has implications for the development of therapies to achieve long-lasting hematologic responses. This article is highlighted in the In This Issue feature, p. 476.