MLL translocation

Residual KMT2A-r before allo-HSCT independently predicts the risk of survival and relapse, and donor lymphocyte infusion or posttransplantation maintenance therapies should be considered for patients who have AML with detectable molecular MRD.

Furthermore, 66s effectively blocked cell proliferation and induced apoptosis and differentiation in leukemia cells harboring MLL1 translocations. Overall, this work provides a high-quality chemical probe targeting the catalytic SET domain of ASH1L with increased inhibitory activity and cellular efficacy to study biological functions of ASH1L and potentially to develop novel anticancer therapeutics.

P2, N=27, Recruiting, University of Illinois at Chicago | Trial completion date: Nov 2024 --> Dec 2026 | Trial primary completion date: Nov 2024 --> Dec 2026

MC180380, an inhibitor of cyclin-dependent kinase 9 (CDK9), is an efficacious anti-cancer agent worth advancing further toward clinical use.

Given the results obtained with menin inhibitors in KMT2A-rearranged and NPM1-mutated AML, our findings open an opportunity for exploiting a therapeutic vulnerability in all HOX-AML including KMT2A-PTD AML or AML with high MEN1 expression. Since HOX-AML highly express genes according to the HOX differentiation profile, stage-specific surface proteins coded by these genes would be promising targets.

In this study, we present the in vivo effectiveness of DS-1594b in combination with venetoclax in a PDX model of NPM1-mutated AML. Moreover, the combination treatment exhibits differentiation-inducing effects, which contribute to its therapeutic effectiveness, and was safe. Overall, our findings strongly indicate that the combination of DS-1594b and venetoclax exhibits promising anti-leukemic activity in vivo and holds potential as a therapeutic strategy for AML patients with mtNPM1 mutations.

As H3K79me2 has a putative oncogenic function in leukemia cells driven by MLL translocations, using CRISPR-ChIP we reveal a functional partitioning of H3K79 methylation into two distinct regulatory units: an oncogenic DOT1L complex directed by the MLL fusion protein in a Menin-dependent manner and a separate endogenous DOT1L complex, where catalytic activity is directed by MLLT10. Overall, CRISPR-ChIP provides a powerful tool for the unbiased interrogation of the mechanisms underpinning chromatin regulation.

identify circular RNAs (circRNAs) derived from mixed lineage leukemia (MLL) breakpoint cluster regions, demonstrating a causal role of circRNAs in MLL translocations. CircRNAs:DNA hybrids (circR-loops) trigger RNA polymerase pausing, driving oncogenic gene fusions via endogenous RNA-directed DNA damage.

Inhibition of BCR-ABL (Imatinib), Flt3 (Quizartinib) or Src-Kinase-Family (Saracatinib) leads to significant reconstitution of SHIP1 protein expression. These results further support a functional role of SHIP1 as tumor suppressor protein and could be the basis for the establishment of a targeted therapy form.

Our study provides a comprehensive resource of ontogeny- and malignancy-driven changes in the intra- and extracellular proteome of haematopoietic progenitor cells, which in combination with the results from our functional assays sheds new light on age-specific targetable pathways in MLLr leukaemia. Acute leukemia, Proteomics, MLL

A steroid pre-phase (Prednisolone 100mg daily for 7 days) was followed by a disease debulking phase of cyclophosphamide 150mg/m 2 BD day 1-3, vincristine 2mg day 1 & 11 and dexamethasone 10mg/m 2 day 1-4 and 11-14...All received intrathecal prophylaxis with methotrexate, cytarabine and hydrocortisone prior to blinatumomab treatment blocks and day 1 and 8 of each B-cycle, total of 8 doses... Blinatumomab with chemotherapy was well tolerated with a high rate of remission and deep MRD responses in the majority of patients. Responses appeared durable with this lower intensity treatment approach despite a low rate of allogeneic stem cell transplantation and the exclusion of anthracyclines and asparaginase from treatment. Despite failing to meet proof-of-concept criteria the EFS and OS were encouragingfor older ALL patients and demonstrates the feasibility of combining low-intensity chemotherapy with blinatumomab in older adults with BCP-ALL.