MLL translocation

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.

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.

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

The Mixed-Lineage Leukaemia (MLL/KMT2A) gene is frequently rearranged in childhood and adult acute leukaemia (AL) and in secondary leukaemias occurring after therapy with DNA topoisomerase targeting anti-cancer agents such as etoposide (t-AL)...However, the t-AL hotspot and the centre of the observed preferential DNA cleavage are offset by over 250 nucleotides, suggesting additional factors contribute to the distribution of t-AL break sites. We review these recent genomic datasets along with older experimental results, analysis of TOP2 DNA cleavage site preferences and DNA secondary structure features that may lead to break site selection in t-AL MLL/KMT2A translocations.

We will also explore how CD47 inhibition may move immunotherapy into front-line settings and unlock new treatment strategies in TP53 mutated disease. We will then consider how these new therapeutic advances may change the management of AML overall.

To interrogate these mechanisms at higher resolution, advances in single-cell techniques have begun to highlight the heterogeneity of epigenomic landscapes and how these impact on gene expression within different AML populations in individual cells. Combined, these technologies provide a new lens through which to study the role of epigenetic modifications in normal hematopoiesis and how the underlying mechanisms can be hijacked in the context of malignancies such as AML.

This is in line with our previous work which shows that IGF2BP3 overexpression leads to progenitor expansion in the mouse marrow and is essential for development of MLL-AF4 induced leukemogenesis. Our work also provides strong rationale for targeting this machinery for therapy in B-ALL.

Conclusion s : We have optimized the method of cell surface protein identification on primary BCP-ALL samples (Fig.1). It allowed us to overcome the technical issues of proteomics analysis of samples from the patients and to identify a subset of surface proteins, which can be promising targets for immunotherapy.

Therapeutically, YEATS containing MLL-ENL leukemic cells display increased sensitivity to the YEATS inhibitor SGC-iMLLT compared to control AML cells. Our results demonstrate that the YEATS domain is important for MLL-ENL fusion protein-mediated leukemogenesis and exposes an "Achilles heel" that may be therapeutically targeted for treating t(11;19) patients.

As anticipated, pinometostat-resistant cells displayed a slight cross-resistance to most chemotherapeutic agents currently used in ALL treatments but became remarkably more sensitive toward the BCL-2 inhibitor venetoclax. Also, our model demonstrates that under prolonged pressure of DOT1L inhibition, KMT2A-rearranged ALL cells seem to initiate a reprogramming process that involves the acquirement (or selection) of myeloid-like characteristics, an ability that may be connected to leukemic lineage switches which are not uncommon in KMT2A-rearranged acute leukemias. Hence, our model represents an important tool to study the complex biology of KMT2A-rearranged leukemia, and its existence and availability requires to be shared with the community.

Finally, we tested IL4I1 expression in response to Fedratinib, a JAK2 inhibitor, and showed that IL4I1 expression was decreased in responders (R) vs nonresponders (NR) (Fig. 2F). We conclude that IL4I1 is a rational immune therapeutic target for AML and testing of IL4I1 Inhibitor CB-668 through a collaboration with Calithera is underway.

Bayesian monitoring of responses begins after the first 10 enrolled patients are evaluable for efficacy. This study is recruiting in the United States and Japan.

Here we show in vitro efficacy of DS-1594b, a selective small molecule menin inhibitor, as single agent or in combination with Venetoclax in MLLr and NPM1 mutated cell lines and primary leukemia samples. Preliminary data demonstrate differentiation effects of DS-1594b as single agent in both cell lines and primary AML leukemia samples. Combination effects show synthetic lethality in almost all cell lines except OCI-AML3.

Front-line therapy for MM was cyclophosphamide, bortezomib, and dexamethasone (CYBORD) followed by autologous stem cell transplant (autoSCT) for all but one patient who received a tandem transplant. Six patients received prior radiation therapy for MM and all but one received lenalidomide as post autoSCT maintenance...Three (16.7%) patients proceeded to alloSCT in first remission while one received alloSCT after salvage chemotherapy with blinatumomab...The median OS of patients with post MM tALL is longer than that of tALL arising after other cancers. With the evolving changes in MM treatment patterns, further and continued evaluation of a larger cohort is recommended.

The KMT2A::USP2 fusion has only been reported in selected cases in the literature, initially in an infant with AML and subsequently in isolated cases of ALL and AML. Since disease prognosis has been reported to be related to the localization of breakpoints, the importance of developing methodologies to detect additional KMT2A fusion partners is highlighted within this case. Intriguingly, the finding of this rare KMT2A fusion across different lineage acute leukemias and our recent report of its presence in MPAL may provide links of a common pathway in myeloid/lymphoid lineage derivation.

Compared with historical data, prognosis of patients with noninfant 11q23/KMT2A-rearranged ALL has improved, but allo-HSCT failed to affect outcome. Targeted therapies are needed to reduce relapse and treatment-related mortality rates.

Nalm6-Cas9_1-6 monoclonal cell line stably expressing highly active Cas9 protein was obtained, which provided a basis for exploring the translocation of MLL in therapy-related leukemias based on CRISPR/Cas9 genome-wide high-throughput genome-wide translocation sequencing.

After 12 cycles of azacitidine treatment, fluorescence in situ hybridization (FISH) for KMT2A split signal indicated that 94% of his bone marrow (BM) cells were positive...The preconditioning regimen consisted of fludarabine, busulfan, melphalan, and antithymocyte globulin (ATG). The graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and short-term methotrexate...The preconditioning regimen and GVHD prophylaxis were the same as those for the first PBSCT without ATG. The patient's PB revealed complete second donor-type chimerism, and the patient has maintained a CR since the second transplantation.

Bayesian monitoring of responses begins after the first 10 enrolled patients are evaluable for efficacy. This study is recruiting in the United States and Japan.

Bayesian monitoring of responses begins after the fi rst 10 enrolled patients are evaluable for effi cacy. This study is recruiting in the United States and Japan.

These may have been otherwise undetected, but can subsequently be confirmed by FISH, and importantly allow the generation of molecular measurable residual disease (MRD) assays to assess treatment response. We conclude that Q30 is a rapid, simple and sensitive adjunct to conventional FISH in the diagnosis of AML and, in combination with CMA, may preclude the requirement for conventional and time consuming G-banding analysis.

Conclusion Molecular profiling of KMT2A -rearranged AML in Russian Federation reveals the highest incidence of KMT2A-MLLT3 fusion gene and KMT2A intron 9 involvement. Our data also confirms the relatively quiet landscape of accompanying mutations in KMT2A-rearranged AML with RAS pathway most frequently involved.

Although silencing Hoxa11 in leukemia cells did not affect Cxcr4 expression, it resulted in increased transwell migration, motility in confined spaces 3 μm in size, and cell protrusion. Our results revealed that Hoxa10 plays an important role in survival and Hoxa11 contributes to MS formation in MLL-t acute myeloid leukemia with activating KRAS mutation.

Although the MLL-SEPT5 fusion transcript was occasionally described in acute myeloid leukemia, it was first identified in MDS. Patients with MLL-SEPT5 fusion gene exhibited a poor prognosis even with an aggressive treatment.

Patients on the strong CYP3A4 inhibitors ketoconazole, itraconazole, or isavuconazole, are excluded unless they can be safely taken off these medications or switched to another antifungal medication at least 7 days prior to start of study treatment. Bayesian monitoring of responses will be started after the first 10 enrolled patients are evaluable for efficacy. Study endpoints are summarized in Table 1.

This method excluded AML associated with the following genetic abnormalities: t(8;21), t(15;17), inv(16), and KMT2A translocation, with 92% sensitivity [95% confidence interval (CI): 78.6%-98.3%] and a 98.5% negative predictive value (95% CI: 90.6%-99.8%). Our data showed that the Compass database-guided analysis could identify phenotypic differences between AML groups, representing a useful tool for the identification of DfN patterns.

Criteria for inclusion were a pathologically confirmed diagnosis of AML, age > 18 years, treatment with either decitabine or azacitidine in combination with venetoclax. In contrast to what has been reported for chemotherapy outcomes and in the ELN classification, the KMT2A-MLLT3 translocation was not associated with improved outcomes when compared to other KMT2A translocations. While this study was limited in being retrospective and having a small and heterogeneous population, our findings suggest that venetoclax and HMA are effective in KMT2A rAML and warrant further investigation.

Compound 63 selectively inhibited MLL histone methyltransferase activity and the proliferation of MLL translocation-harboring cells. Furthermore, 63 displayed good pharmacokinetic properties and suppressed the growth of MV4-11 xenograft tumors in mice after oral administration, first verifying the in vivo efficacy of targeting the WDR5-MLL1 PPI by small molecules.

M-1121 is orally bioavailable and shows potent antitumor activity in vivo with tumor regressions observed at tolerated doses in the MV4;11 subcutaneous and disseminated models of MLL-rearranged leukemia. Together, our findings support development of an orally active covalent menin inhibitor as a new therapy for MLLr leukemia.

MLLT1 undergoes phase separation to enhance recruitment of the super elongation complex (SEC) and drive transcription. Mutations in MLLT1 observed in Wilms tumor patients enhance phase separation and transcription to drive an aberrant gene expression program.

Furthermore, the results of a meta‑analysis using Heuser's AML dataset supported the finding that chemotherapy responders have higher expression levels of HOXA11. These results indicated that the expression of HOXA11 increased cell apoptosis and predicted an improved response to Ara‑C in AML.