There are only a few options for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), thus, this is a major area of unmet medical need. In this study, we reveal that the inclusion of a poison exon in RBM39, which could be induced by both CDK9 or CDK9 independent cyclin-dependent kinases, mitogen-activated protein kinases, glycogen synthase kinases, CDC-like kinases (CMGC) kinase inhibition, is recognized by the nonsense-mediated messenger RNA decay pathway for degradation. Targeting this poison exon in RBM39 with CMGC inhibitors led to protein downregulation and the inhibition of ALL growth, particularly in relapsed/refractory B-ALL. Mechanistically, disruption of cotranscriptional splicing by the inhibition of CMGC kinases, including DYRK1A, or inhibition of CDK9, which phosphorylate the C-terminal domain of RNA polymerase II (Pol II), led to alteration in the SF3B1 and Pol II association. Disruption of SF3B1 and the transcriptional elongation complex altered Pol II pausing, which promoted the inclusion of a poison exon in RBM39. Moreover, RBM39 ablation suppressed the growth of human B-ALL, and targeting RBM39 with sulfonamides, which degrade RBM39 protein, showed strong antitumor activity in preclinical models. Our data reveal that relapsed/refractory B-ALL is susceptible to pharmacologic and genetic inhibition of RBM39 and provide 2 potential strategies to target this axis.

Iron regulatory proteins (IRP1 and IRP2) play a pivotal role in maintaining cellular iron homeostasis by binding to iron-responsive elements (IREs) of target messenger RNAs and regulating the expression of these iron-related genes. Mice and humans who lack functional IRP1 develop erythrocytosis due to erythropoietin (EPO) overproduction, whereas those who lack IRP2 develop microcytic anemia, believed to result from iron deficiency of erythroblasts. Here, we discovered that IRP2 deficiency reduced the expression of hypoxia-inducible factor 2α (HIF2α) and its transcriptional target, EPO, thereby compromising the stress erythropoiesis response to generate red blood cells upon anemia. The distinct consequences of IRP2 and IRP1 on EPO result from the higher binding affinity of the HIF2α IRE for IRP1 than IRP2. This difference in binding affinity arises from a bulge uridine in the upper stem of HIF2α IRE that impairs the ability of IRP2 to bind the IRE. These results reveal that IRP1 and IRP2 play distinct roles in erythropoiesis and unveil an unsuspected IRE binding preference that contributes to the divergent phenotypes observed in IRP1- and IRP2-deficient mammals.

Pretransplant detection of KMT2Ar measurable residual disease ≥0.001% by quantitative polymerase chain reaction was associated with significantly inferior posttransplant survival (2-year relapse-free survival 17% vs 59%; P = .001) and increased 2-year cumulative incidence of relapse (75% vs 25%, P = .0004).

Neurovascular complications, including strokes and transient ischemic attacks (TIAs), are common and cause significant morbidity in individuals with sickle cell disease (SCD). The Stroke Prevention Trial in Sickle Cell Anemia (STOP) (1998) established chronic transfusions as the standard of care for children with SCD at high risk for stroke. Using statewide data from the California Department of Health Care Access and Innovation (1991-2019), we determined the cumulative incidence (CMI) and rates of primary and recurrent strokes/TIAs in people with SCD pre- and post-STOP trial. For the 7636 patients included in our SCD cohort, the cumulative incidence of the first ischemic stroke was 2.1% by the age of 20 years and 13.5% by the age of 60 years. The CMI of the first intracranial hemorrhage (ICH) was 0.5% and 6.8% by the age of 20 and 60 years, respectively. Ischemic stroke rates increased in children (age <18 years; 234.9 vs 165.1 per 100 000 patient years [PY]; P = .012) and adults (age 31-50 years; 431.1 vs 303.2 per 100 000 PY; P = .031) in 2010 to 2019 when compared with the preceding decade. There was an increase in the rates of ICH in those aged 18 to 30 years and TIA in children <18 years from 2010 to 2019 when compared with the previous decade. Risk factors for strokes included increasing age, hypertension, and hyperlipidemia. These findings underscore the need for stroke prevention in adults with SCD, suggesting an emphasis on management of modifiable cerebrovascular risk factors that have been proven to be effective in the general population.

Before the advent of effective iron chelation, death from iron-induced cardiomyopathy and endocrine failure occurred in the second decade in patients with thalassemia major, and this experience has driven expectation of poor outcomes and caused anxiety in all disorders associated with iron loading to this day. To be clear, severe iron overload still causes significant morbidity and mortality in many parts of the world, but current understanding of iron metabolism, noninvasive monitoring of organ-specific iron loading in humans, and effective iron chelators have dramatically reduced morbidity of iron overload. Furthermore, clinical experience in hemoglobinopathies supports iron biology learned from animal studies and identifies common concepts in the biology of iron toxicity that inform the management of iron toxicity in several human disorders. The resultant significant increase in survival uncovers new complications due to much longer exposure to anemia and to iron, which must be considered in long-term therapeutic strategies. This review will discuss the management of iron toxicity in patients with hemoglobinopathies and transfusion-dependent anemias and how iron biology informs the clinical approach to treatment.

Quantitative immunoprecipitation mass spectrometry (QIP-MS) allows the identification of the M-protein in patients with multiple myeloma (MM) otherwise in complete response, and could be considered suitable for measurable residual disease (MRD) evaluation in peripheral blood. In the context of the GEM2012MENOS65 and GEM2014MAIN trials, we compared the performance of QIP-MS in serum with next-generation flow (NGF) cytometry in bone marrow to assess MRD in paired samples obtained postinduction, transplant, consolidation and after 24 cycles of maintenance. At each time point, both NGF and QIP-MS were able to segregate 2 groups of patients with significantly different progression-free survival; when the evolution of the results obtained with either method was considered, maintaining or converting to MRD negativity was associated with longer survival, significantly better when compared with sustaining or converting to MRD positivity. Reemergence of MRD by QIP-MS was associated with high risk of imminent clinical progression. In conclusion, MRD evaluation by NGF and MS achieves similar prognostic value based in single time point assessments and kinetics. Thus, the minimally invasive nature of MRD monitoring by MS represents a breakthrough in highly sensitive response assessment in MM. The trials were registered at www.clinicaltrials.gov as #NCT01916252 (GEM2012MENOS65) and at EudraCT as #2012-005683-10; and as #NCT02406144 (GEM2014MAIN) and at EudraCT as 2014-00055410.

A "restrictive" red blood cell transfusion threshold, a hemoglobin concentration <7 to 8 g/dL, has long been recommended for most hospitalized patients including anemic patients with stable cardiovascular disease (CVD). Although no threshold recommendation is given for acute coronary syndromes (ACSs), recent evidence suggests that "liberal" rather than "restrictive" transfusion strategies are associated with significantly improved safety for hospitalized patients with stable CVD and/or ACS. This finding suggests that previously available data were misinterpreted. Conclusions drawn from earlier transfusion trigger trials have been confounded by unintentional trial design and analysis flaws that have contributed to erroneous recommendations regarding the safety of a restrictive threshold. Subsequently, these conclusions have been incorporated into widely accepted guidelines and clinical practice. Management with a restrictive vs liberal transfusion strategy (<10 g/dL) increases the risk of new-onset ACS in patients with CVD by ∼2%. We estimate that since 2019, using hospital databases and a recent meta-analysis, this practice may have resulted in ∼700 excess ACS events per year in orthopedic surgical patients. Given these findings, transfusion practices in other clinical conditions, particularly those derived from similar transfusion trigger trials, should be questioned. Restrictive and liberal transfusion policies merit a general reconsideration. Rather than a single numerical transfusion trigger, transfusion therapy should be personalized. Consideration of an individual patient's age, clinical status, and comorbidities is integral to transfusing. To avoid making similar errors, future trials of transfusion therapy should determine common practices before study inception and incorporate them as a usual-care "control" comparator arm into the trial design. Such studies should more reliably improve current transfusion practice.