Glutamine dependency has been shown to be a metabolic vulnerability in acute myeloid leukemia (AML). Prior studies using several in vivo AML models showed that depletion of plasma glutamine, induced by long-acting crisantaspase (pegcrisantaspase [PegC]) was synergistic with the B-cell lymphoma-2 (BCL-2) inhibitor venetoclax (Ven), resulting in significantly reduced leukemia burden and enhanced survival. Here, we report a phase 1 study of the combination of Ven and PegC (VenPegC) for treating adult patients with relapsed or refractory AML, including patients who had previously received Ven. The primary end points were the incidence of regimen-limiting toxicities (RLTs) and the maximum tolerated dose (MTD). Twenty-five patients received at least 1 PegC dose with Ven, and 18 efficacy-evaluable patients completed at least 1 VenPegC cycle; 12 (67%) had previously received Ven. Hyperbilirubinemia was the RLT and occurred in 60% of patients treated with VenPegC; 20% had grade ≥3 bilirubin elevations. MTD was determined to be Ven 400 mg daily with biweekly PegC 750 IU/m2. The most common treatment-related adverse events of any grade in 25 patients who received VenPegC included antithrombin III decrease (52%), elevated transaminases (36%-48%), fatigue (28%), and hypofibrinogenemia (24%). No thromboembolic or hemorrhagic adverse events or clinical pancreatitis were observed. The overall complete remission rate in efficacy-evaluable patients was 33%. Response correlated with alterations in proteins involved in messenger RNA translation. In patients with RUNX1 mutations, the composite complete remission rate was 100%. This study was registered at www.ClinicalTrials.gov as #NCT04666649.

The liver hormone hepcidin regulates systemic iron homeostasis to provide enough iron for vital processes while limiting toxicity. Hepcidin acts by degrading its receptor ferroportin (encoded by Slc40a1) to decrease iron export to plasma. Iron controls hepcidin production in part by inducing liver endothelial cells (LECs) to produce bone morphogenetic proteins (BMPs) that activate hepcidin transcription in hepatocytes. Here, we used in vitro and in vivo models to investigate whether ferroportin contributes to LEC intracellular iron content to modulate BMP expression and, thereby, hepcidin. Quantitative proteomics of LECs from mice fed different iron diets demonstrated an inverse relationship between dietary iron and endothelial ferroportin expression. Slc40a1 knockdown primary mouse LECs and endothelial Slc40a1 knockout mice exhibited increased LEC iron and BMP ligand expression. Endothelial Slc40a1 knockout mice also exhibited altered systemic iron homeostasis with decreased serum and total liver iron but preserved erythropoiesis. Although endothelial Slc40a1 knockout mice had similar hepcidin expression to control mice, hepcidin levels were inappropriately high relative to iron levels. Moreover, when iron levels were equalized with iron treatment, hepcidin levels were higher in endothelial Slc40a1 knockout mice than in controls. Finally, LEC ferroportin levels were inversely correlated with hepcidin levels in multiple mouse models, and treatment of hepcidin-deficient mice with mini-hepcidin decreased LEC ferroportin expression. Overall, these data show that LEC ferroportin modulates LEC iron and consequently BMP expression to influence hepcidin production. Furthermore, LEC ferroportin expression is regulated by hepcidin, demonstrating a bidirectional communication between LECs and hepatocytes to orchestrate systemic iron homeostasis.

During the transition from embryonic to adult life, the sites of hematopoiesis undergo dynamic shifts across various tissues. In adults, although bone marrow (BM) becomes the primary site for definitive hematopoiesis, the establishment of the BM niche for accommodating hematopoietic stem cells (HSCs) remains incompletely understood. Here, we reveal that perinatal BM mesenchymal stem cells (BMSCs) exhibit highly activated insulin-like growth factor 1 receptor (IGF1R) signaling compared with adult BMSCs (aBMSCs). Deletion of Igf1r in perinatal BMSCs (pBMSCs) hinders the transition of HSCs from the fetal liver to the BM in perinatal mice and disrupts hematopoiesis in adult individuals. Conversely, the deletion of Igf1r in aBMSCs, adipocytes, osteoblasts, or endothelial cells does not affect HSCs in the BM. Mechanistically, IGF1R signaling activates the transcription factor nuclear factor of activated T cells c1 in pBMSCs, which upregulates CXCL12 and other niche factors for HSC retention. Overall, IGF1R signaling in pBMSCs regulates the development of the BM niche for hematopoiesis.

Both the 2022 World Health Organization Classification of Hematolymphoid Tumors, 5th Edition and the International Consensus Classification of lymphoma have refined the way we now approach high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements moving the previous generation of classification a step forward. The unifying biology of MYC/BCL2 tumors has become clearer and their inferior prognosis confirmed compared with those with morphologic similar phenotypes but lacking the classifcation defining cytogenetic abnormalities. Fluorescent in situ hybridization testing has now become largely population based, and we have learned much from this. We can readily define molecular categories and apply these widely to clinical practice. Uncertainty has, however, been shed on the place of MYC/BCL6 translocations in defining a common disease group of double hit lymphoma due to biological heterogeneity. We have enhanced our knowledge of outcomes and the role of therapy intensification to overcome chemotherapy resistance in HGBL. For those patients failed by initial induction chemotherapy, immunotherapy approaches, including chimeric antigen receptor T-cell therapies, are improving outcomes. Novel inhibitors, targeting dysregulated oncogenic proteins, are being explored at pace. The rare, but difficult, diagnostic classification HGBL (not otherwise specified) remains a diagnosis of exclusion with limited data on an optimal clinical approach. The days of talking loosely of double- and triple-hit lymphoma are numbered as biology and outcomes may not be shared. This review synergizes the current data on biology, prognosis, and therapies in HGBL.

The US Food and Drug Administration announcement in November 2023 regarding reports of the occurrence of secondary T-cell lymphomas in patients receiving chimeric antigen receptor T cells (CAR-Ts) for B-cell malignancies resulted in widespread concern among patients, clinicians, and scientists. Little information relevant to assessing causality, most importantly whether CAR retroviral or lentiviral vector genomic insertions contribute to oncogenesis, was initially available. However, since that time, several publications have provided clinical and molecular details on 3 cases showing clonal CAR vector insertions in tumor cells but without firm evidence these insertions played any role in oncogenic transformation. In addition, several other cases have been reported without vector detected in tumor cells. In addition, epidemiologic analyses as well as institutional long-term CAR-T recipient cohort studies provide important additional information suggesting the risk of T-cell lymphomas after CAR-T therapies is extremely low. This review will provide a summary of information available to date, as well as review relevant prior research suggesting a low susceptibility of mature T cells to insertional oncogenesis and documenting the almost complete lack of T-cell transformation after natural HIV infection. Alternative factors that may predispose patients treated with CAR-Ts to secondary hematologic malignancies, including immune dysfunction and clonal hematopoiesis, are discussed, and likely play a greater role than insertional mutagenesis in secondary malignancies after CAR therapies.

Despite advancements in new treatments, management of older patients with acute lymphoblastic leukemia (ALL) remains an unmet medical need. With increasing age, patients with ALL have a significantly lower complete remission rate, higher early mortality and relapse rate, and poorer survival than younger patients. This is attributed to a higher prevalence of adverse prognostic factors among older individuals and reduced tolerance to chemotherapy. Progress has been made in tailoring moderately intensive chemotherapy protocols for Philadelphia chromosome (Ph)/BCR::ABL-negative ALL in older patients, and recent phase 2 studies have explored integrating immunotherapy into initial treatment with very promising results. However, establishing new standard regimens for this age group remains and improving general management strategy is a pending task.

Nuclear receptor TR4 (NR2C2) was previously shown to bind to the -117 position of the γ-globin gene promoters in vitro, which overlaps the more recently described BCL11 transcription factor A (BCL11A) binding site. The role of TR4 in human γ-globin gene repression has not been extensively characterized in vivo, whereas any relationship between TR4 and BCL11A regulation through the γ-globin promoters is unclear at present. We show here that TR4 and BCL11A competitively bind in vitro to distinct, overlapping sequences, including positions overlapping -117 of the γ-globin promoter. We found that TR4 represses γ-globin transcription and fetal hemoglobin accumulation in vivo in a BCL11A-independent manner. Finally, examination of the chromatin occupancy of TR4 within the β-globin locus, compared with BCL11A, shows that both bind avidly to the locus control region and other sites, but only BCL11A binds to the γ-globin promoters at statistically significant frequency. These data resolve an important discrepancy in the literature and, thus, clarify possible approaches to the treatment of sickle cell disease and β-thalassaemia.

Abnormalities involving class I HLA are frequent in many lymphoma subtypes but have not yet been extensively studied in cutaneous T-cell lymphomas (CTCLs). We characterized the occurrence of class I HLA abnormalities in 65 patients with advanced mycosis fungoides or Sézary syndrome. Targeted DNA sequencing, including coverage of HLA loci, revealed at least 1 HLA abnormality in 26 of 65 patients (40%). Twelve unique somatic HLA mutations were identified across 9 patients, and loss of heterozygosity or biallelic loss of HLA was found to affect 24 patients. Although specific HLA alleles were commonly disrupted, these events did not associate with a decrease in the total class I HLA expression. Genetic events preferentially disrupted HLA alleles capable of presenting greater numbers of putative neoantigens. HLA abnormalities co-occurred with other genetic immune evasion events and were associated with worse progression-free survival. Single-cell analyses demonstrated that HLA abnormalities were frequently subclonal. Through analysis of serial samples, we observed that disrupting class I HLA events change dynamically over the disease course. The dynamics of HLA disruption are highlighted in a patient who received pembrolizumab and in whom resistance to pembrolizumab was associated with the elimination of an HLA mutation. Overall, our findings show that genomic class I HLA abnormalities are common in advanced CTCL and may be an important consideration in understanding the effects of immunotherapy in CTCL.