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In this Perspective, Yong and Toh present a novel model of coagulation that integrates recent insights into the close connection between coagulation and innate immunity. The authors integrate traditional models of the coagulation cascade and the cellular schema supporting and activating coagulation with newer concepts of an intersection between clotting and the inflammatory and immune response to injury.


Familial platelet disorder with associated myeloid malignancy (FPDMM), a rare syndrome of thrombocytopenia, abnormal platelet function, and predisposition to myeloid malignancy, is caused by mutations in the RUNX1 gene. In this month’s CME article, Cunningham et al report on the first 111 patients derived from 45 unrelated families enrolled in the National Institutes of Health–initiated FPDMM natural history study between 2019 and 2021. The authors confirm the major features of the disease and add allergic and gastrointestinal symptoms to the catalog. This longitudinal study offers a valuable resource for further study of this rare disease.


T-cell acute lymphoblastic leukemia (T-ALL) has a high prevalence of activated Notch signaling, but Notch-1 inhibitors have proven excessively toxic in clinical studies. Melnick et al investigate cell division cycle 73 (Cdc73), a Notch cofactor and component of RNA polymerase-associated transcription, as a possible indirect target to inhibit Notch-deregulated T-ALL. The authors demonstrate that Cdc73 interacts with Notch and enhances transcription of genes facilitating DNA repair and oxidative phosphorylation, suggesting it likely is a candidate target for treating Notch-deregulated T-ALL.


Growth factor independence 1 (GFI1) is a key transcriptional regulator of hematopoiesis. A germ line GFI1 variant, GFI1-36N, is present in 5-7% of Caucasians but is enriched to 10-15% in patients with acute myeloid leukemia (AML). Frank and colleagues delineate that GFI1-36N cells have increased mutational burden and chromosomal aberrations and also evince impaired DNA repair. The authors identify O6-methylguaninine-DNA-methyltransferase (MGMT) as a downstream target of GFI1-36N. Combination of the MGMT inhibitor temozolomide and a PARP inhibitor kills GIF1-36N–associated AML cells, suggesting a potential novel therapy for GFI1-36N–associated AML.

The success of tyrosine kinase inhibitors (TKIs) as treatment for chronic myeloid leukemia (CML) has fueled an ambition to establish criteria for treatment-free remission (TFR). Pagani and colleagues used sensitive measurable residual disease (MRD) detection methods to predict relapse after TKI discontinuation. Median BCR::ABL1 DNA detected in granulocytes was predictive of relapse (100%). Patients with CML with undetectable granulocyte MRD were further stratified by detection of MRD in T cells with T-cell positivity predicting 67% relapse; among patients with negative MRD in both granulocytes and T cells, relapse was only 25%. These results lay a groundwork for safer choice of patients for TFR.


Erythropoiesis relies on transcriptional regulation through modulation of the level and activity of RNA polymerase II (RNAPII). Lv et al elucidate a key role of HEXIM1 in these transcriptional pathways. HEXIM1 interacts with positive transcription factor β, which regulates RNAPII progression and pausing during transcription. HEXIM1 has been recognized as a negative regulator of RNAPII. Here, the authors demonstrate that HEXIM1 has a dual role in erythropoiesis, in that it also positively regulates RNAPII localization and differential transcriptional activity at the γ-globin and β-globin loci, suggesting modulation of HEXIM1 could be a therapeutic target to increase fetal hemoglobin.





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