Regulation of MLL/COMPASS stability through its proteolytic cleavage by taspase1 as a possible approach for clinical therapy of leukemia.

Chromosomal translocations of the Mixed-lineage leukemia 1 (MLL1) gene generate MLL chimeras that drive the pathogenesis of acute myeloid and lymphoid leukemia. The untranslocated MLL1 is a substrate for proteolytic cleavage by the endopeptidase threonine aspartase 1 (taspase1); however, the biological significance of MLL1 cleavage by this endopeptidase remains unclear. Here, we demonstrate that taspase1-dependent cleavage of MLL1 results in the destabilization of MLL. Upon loss of taspase1, MLL1 association with chromatin is markedly increased due to the stabilization of its unprocessed version, and this stabilization of the uncleaved MLL1 can result in the displacement of MLL chimeras from chromatin in leukemic cells. Casein kinase II (CKII) phosphorylates MLL1 proximal to the taspase1 cleavage site, facilitating its cleavage, and pharmacological inhibition of CKII blocks taspase1-dependent MLL1 processing, increases MLL1 stability, and results in the displacement of the MLL chimeras from chromatin. Accordingly, inhibition of CKII in a MLL-AF9 mouse model of leukemia delayed leukemic progression in vivo. This study provides insights into the direct regulation of the stability of MLL1 through its cleavage by taspase1, which can be harnessed for targeted therapeutic approaches for the treatment of aggressive leukemia as the result of MLL translocations.

Functional specificity of CpG DNA-binding CXXC domains in mixed lineage leukemia.

The MLL CXXC domain binds nonmethylated CpG-containing DNA and is essential for the oncogenic properties of MLL fusion proteins. To determine potential functional promiscuity of similar DNA binding domains, we replaced the MLL CXXC domain in the context of the leukemogenic MLL-AF9 fusion with CXXC domains from DNMT1, CGBP (CFP1), and MBD1, or with a methyl-CpG-binding domain (MBD) from MBD1. MLL(DNMT1 CXXC)-AF9 shows robust in vitro colony forming activity and in vivo leukemogenesis, similar to MLL-AF9. However, colony forming ability and leukemogenicity are abrogated in MLL-AF9 containing either the CGBP or MBD1 CXXC domains or the MBD1 MBD domain. Direct comparison of in vitro DNA binding affinity of the isolated CXXC or MBD domains demonstrated that MLL, DNMT1, and CGBP CXXC domains could each bind to unmethylated DNA but with differing affinity. In contrast, the isolated MBD1 CXXC and MBD1 MBD domains were unable to bind to the same DNA. However, all substituted domains still allowed targeting of the MLL fusions to the functionally important Hoxa9 locus in primary bone marrow progenitor cells. In addition to DNA binding activity, it was critical that specific CpG residues in the Hoxa9 locus were protected from methylation for leukemia development. This ultimately prevented histone 3 lysine 9 trimethylation (H3K9me3) of the locus and enabled Hoxa9 expression. These were properties shared by MLL and DNMT1 CXXC domains but not by CGBP CXXC or the other swapped fusions tested. We demonstrate that similar CXXC domains can be mechanistically distinguished by specificity of CpG nucleotides preferentially protected from DNA methylation.

Does High-Dose Thromboprophylaxis Improve Outcomes in COVID-19 Patients? A Meta-analysis of Comparative Studies.

Background Thromboembolism remains a detrimental complication of novel coronavirus disease (COVID-19) despite the use of prophylactic doses of anticoagulation Objectives This study aimed to compare different thromboprophylaxis strategies in COVID-19 patients Methods We conducted a systematic database search until June 30, 2022. Eligible studies were randomized (RCTs) and nonrandomized studies that compared prophylactic to intermediate or therapeutic doses of anticoagulation in adult patients with COVID-19, admitted to general wards or intensive care unit (ICU). Primary outcomes were mortality, thromboembolism, and bleeding events. Data are analyzed separately in RCTs and non-RCTs and in ICU and non-ICU patients. Results. We identified 682 studies and included 53 eligible studies. Therapeutic anticoagulation showed no mortality benefit over prophylactic anticoagulation in four RCTs (odds ratio [OR] = 0.67, 95% confidence interval [CI], 0.18-2.54). Therapeutic anticoagulation didn't improve mortality in ICU or non-ICU patients. Risk of thromboembolism was significantly lower among non-ICU patients who received enhanced (therapeutic/intermediate) anticoagulation (OR = 0.21, 95% CI, 0.06-0.74). Two additional RCTs (Multiplatform Trial and HEP-COVID), not included in quantitative meta-analysis, analyzed non-ICU patients, and reported a similar benefit with therapeutic-dose anticoagulation. Therapeutic anticoagulation was associated with a significantly higher risk of bleeding events among non-randomized studies (OR = 3.45, 95% CI, 2.32-5.13). Among RCTs, although patients who received therapeutic-dose anticoagulation had higher numbers of bleeding events, these differences were not statistically significant. Studies comparing prophylactic and intermediate-dose anticoagulation showed no differences in primary outcomes. Conclusion There is a lack of mortality benefit with therapeutic-dose over prophylactic-dose anticoagulation in ICU and non-ICU COVID-19 patients. Therapeutic anticoagulation significantly decreased risk of thromboembolism risk in some of the available RCTs, especially among non-ICU patients. This potential benefit, however, may be counter balanced by higher risk of bleeding. Individualized assessment of patient's bleeding risk will ultimately impact the true clinical benefit of anticoagulation in each patient. Finally, we found no mortality or morbidity benefit with intermediate-dose anticoagulation.

The role of histone modifications in leukemogenesis.

Histone modifications play a critical role in coordinating accurate gene expression. Aside from genetic mutations which cause altered DNA sequence, it has become increasingly clear that aberrant post-translational modifications of histone tails are also associated with leukemogenesis. The functional roles of specific histone marks has informed the basis of our understanding for underlying mechanisms of leukemia, while global analyses of interacting histone modifications has begun to distinguish subtypes of leukemia with prognostic and therapeutic implications. In this current era of personalized and precision medicine, it will be necessary to not only identify the specific genetic mutations present in a patient's leukemia but to also appreciate the dynamic chromatin states which are driven by histone modifications that can aid our diagnostic and therapeutic strategies for improved management of leukemia.

Glycogen synthase kinase-3 and leukemia: restoring the balance.

The role of GSK-3 in oncogenesis is paradoxical, acting as a tumor suppressor in some cancers and potentiating growth in others. In this issue of Cancer Cell, Wang et al. provide some mechanistic insight into GSK-3 activity's role in potentiating leukemias which are dependent on homeobox (HOX) gene misregulation.