CBFB (Core-Binding Factor Subunit Beta 2)

Not achieving complete remission after induction 2 was found to be an independent prognostic factor for OS and EFS. These findings indicate that genetic abnormalities could be considered stratification factors, predict patient outcomes, and imply the application of targeted therapy.

Mechanistically, CBF-β loss leads to upregulation of type I interferon signalling, and we uncover a direct inhibitory role for CBF-β at the STING locus controlling Interferon Stimulated Gene expression. Targeting CBF-β in kidney cancer both selectively induces tumour cell lethality and promotes activation of type I interferon signalling.

Consistent with this, treatment of tumour cells with a membrane-permeable zinc chelator had no impact on tumour cell viability alone, but significantly increased tumour cell lysis by CD8+ T cells in a TNF-dependent but perforin-independent manner. These results underscore the crucial role of intracellular zinc in regulating tumour cell susceptibility to T cell-mediated killing, revealing a novel vulnerability in tumour cells that might be exploited for the development of future cancer immunotherapeutics.

Specially, CBD was demonstrated to be a molecular glue skeleton facilitating the heterodimerization of RUNX3 with its transcriptional chaperone core-biding factor β (CBFβ) thereby promoting their nuclear localization and the subsequent transactivation of GPX4 and LILRB3. In short, our study provides an alternative strategy to counteract IR-induced enteritis during the radiotherapy on abdominal/pelvic neoplasms.

Importantly, pharmacological inhibition of BCAT1 using the specific inhibitor Gabapentin demonstrated therapeutic effects, as evidenced by delayed leukaemia progression and improved survival in vivo. In conclusion, our study uncovers BCAT1 as a genetic vulnerability and a promising targeted therapeutic opportunity for CBF-AML.

The genetic and molecular abnormalities of primary MS can be detected by FISH and NGS techniques. FLT3-ITD, RUNX1, ASXL1 or TP53 mutation indicates a worse prognosis, but further clinical studies are needed to confirm it.

Our model based on the fusion gene is a prognostic biomarker for non-APL pediatric patients with AML. The nomogram score can provide personalized prognosis prediction, thereby benefiting clinical decision-making.

Patients in CBF-AML group chosen different induction scheme were divided into group A (fludarabine, cytarabine, granulocyte colony stimulating factor and idarubicin (FLAG-IDA) scheme, 134 cases) and group B (daunorubicin, cytarabine and etoposide (DAE) scheme, 55 cases). The prognosis of AML1-ETO was similar to that of CBFβ-MYH11. The selection of induction regimen group FLAG-IDA for high white blood cell count and additional chromosome abnormality can improve the prognosis.

Our findings suggest Latino children are more likely to have a favorable cytogenetic subtype than NLW children, which suggests disparities in outcomes are not primarily due to underlying differences in prognostic subtypes. Additional analyses of pediatric AML as it relates to cytogenetic subtypes and race/ethnicity is ongoing, including the incorporation of disease response and treatment outcomes, to understand how these factors may impact disparities in outcomes.

Overall, our study shows the importance of performing functional assays to aid RUNX1 variant classification and to facilitate the study of FPDMM pathogenesis. We are currently analyzing the platelet proteome data of FPDMM patients by LC-MS/MS, which will be reported at the annual meeting.

Current analysis indicated that addition of HHT can benefit young AML patients in the D5-PBCR (+) group. Complete follow-up combining with cytogenetic-molecular information can provide more reliable results. 1.

We have determined that the combination of VEN plus HAG is safety and HHT at doses of 1, 2 and 3mg/m2 was well tolerated. No DLTs were observed, and the most common Grade 3 non-hematological toxicity were febrile neutropenia.

All patients received decitabine 20 mg/ (m2·d) ×5 days, intravenous; combined with idarubicin 5 mg/ (m2·d), qod×3 times, intravenous; cytarabine 10 mg/ (m2·d), q12h×10 days, subcutaneous; granulocyte stimulating factor 5μg/ (kg·d), qd×10 days, intravenous. Decitabine combined with low-dose chemotherapy is a favorable benefit-risk profile and may be a promising option for refractory/relapsed AML in children. Hematopoietic stem cell transplantation after remission can improve survival rate.

We are currently performing chromatin immunocleavage sequencing using the same cell population to determine RUNX1 binding in vivo. Overall, this study explores a novel regulatory mechanism of RUNX1 function through DNA methylation, and ultimately a new role for RUNX1 in the pathogenesis of inv(16) AML.

No abstract available

She had an aggressive clinical course following initiation of cytarabine-based induction chemotherapy. The underlying mutational landscape may significantly influence the biological behaviour of otherwise favourable risk of CBF-AML cases.

In this study we identified modulators of the response to the PI3K-alpha-specific inhibitor, BYL719, in PIK3CA mutant GCs...Our data provide clear mechanistic insights into PI3K-alpha inhibitor response in PIK3CA mutant gastric tumors and can inform future work as mutant selective inhibitors are in development for diverse tumor types. Implications: Loss of either NEDD9 or BCL-XL confers hyper-sensitivity to PI3K-alpha inhibition while loss of CBFB confers resistance through a CBFB/PIM1 signaling axis.

In these two examples, the molecular abnormality allows us to better define the pathophysiology of leukemia, to adapt certain treatments (all-transretinoic acid, for example), and to follow up the residual disease of strong prognostic value beyond the simple threshold of less than 5% of marrow blasts, signaling the complete remission. However, the new sequencing techniques of the next generation open up broader perspectives by being able to analyze several dozens of molecular abnormalities, improving all levels of management, from diagnosis to prognosis and treatment, even if it means that morphological aspects are increasingly relegated to the background.

The common grades 3-4 adverse events were nausea (100%), thrombocytopenia (39%) and neutropenia (37.5%). The CAG regimen may have activity in CBF-AML patients and could provide a new option for patients who have a poor molecular response to high/intermediate-dose cytarabine.

In our study t(8; 21)(q22; q22) was found in 6% of AML patients. The additional chromosomal abnormalities associated with t(8; 21)(q22; q22), namely loss of Y, monosomy 20 and del(9q), were found in 63% of cases. Presence of the additional/secondary chromosomal aberrations in leukemic cells with t(8; 21)(q22; q22) is the sign of clonal evolution and disease progression.

These results indicated the efficacy of RNA-seq using FFPE-derived RNA as a clinical routine for detecting fusion genes, which can be used as markers for risk stratification in MS.

These data strongly suggest that temporary inhibition of RUNX1/ETO results in long-term restriction of leukaemic self-renewal. Our results provide proof for the feasibility of targeting RUNX1/ETO in a pre-clinical setting and support the further development of siRNA-LNPs for the treatment of fusion gene-driven malignancies.

Therefore, such studies need to be integrated with an in-depth understanding of both the normal and corrupted function in mammary cells to begin to tease out how loss or gain of function can alter the cell phenotype and contribute to disease progression. We review how alterations to RUNX/CBFβ function contextually ascribe to breast cancer subtypes and discuss how the in vitro analyses and mouse model systems have contributed to our current understanding of these proteins in the pathogenesis of this complex set of diseases.

The genomic landscape and clinical characteristics of AML patients with CBFβ-MYH11 are different from patients with RUNX1-RUNX1T1 .

The 5-year event-free survival (EFS), overall survival (OS), and relapse rates were 74.8%, 85.0%, and 13.9%, respectively. There was a significant difference in 5-year OS (100% vs. 81.5%, P = 0.016), EFS (96.4% vs. 67.1%, P = 0.003), and relapse-free survival (RFS) (96.4% vs. 68.8%, P = 0.005) between patients who underwent HSCT in CR1 and those treated with chemotherapy alone.Conclusion : Our data suggest a potential benefit of HSCT for selected patients with CBF-AML and reveal a need to improve risk stratification for pediatric CBF-AML.

Importantly, inhibition of RUNX1 activity spares normal hematopoiesis. Our results suggest that chemical intervention in the RUNX1 program may provide a therapeutic opportunity in ALL.

The multicenter study showed that the most common fusion gene in these 546 children with AML was AML1-ETO, KMT2A-rearrangement and the CBFβ-MYH11 respectively. The most common mutant gene in was WT1.,C-Kit, ASXL1 and FLT3-ITD respectively. Althought only underwent 4 courses of chemotherapy, the OS and LFS could be reached to 77.4±2.6% and 73.7±2.6%.

IFN-α-2b as maintenance therapy for CR1 patients with favorable-risk AML gain a high rate of MRD negative conversion and high rate of 2-year RFS Interferon therapy is safe and well-tolerated.

MOM returned a therapeutic strategy based on the FLT3, CBFβ-MYH11, and NRAS status, which predicted AML patient response to Quizartinib, Trametinib, Selumetinib, and Crizotinib. We successfully validated the results in three different large-scale screening experiments. We believe that XAI will help healthcare providers and drug regulators better understand AI medical decisions.

Moreover, we show that coactivator CARM1 interacts with AETFC and facilitates gene activation by AETFC. Collectively, this study describes a role of oncoprotein LYL1 in AETFC assembly and gene activation by recruiting CARM1 to chromatin for AML cell survival.

Using whole genome and Sanger sequencing, the breakpoints were identified as being located in intron 5 of CBFB and intron 7 of PPP1R7. A microhomology of CAG was found in the break and reconnection sites of CBFB and PPP1R7, thus supporting the formation of CBFB::PPP1R7 by microhomology-mediated end joining.

To quantify epithelial-mesenchymal heterogeneity within tumors, we develop an advanced multiplexed immunostaining approach using SUM149-derived orthotopic tumors and find that the EMT state and epithelial-mesenchymal heterogeneity are predictive of overall survival in a cohort of stage III breast cancer. Our model reveals previously unidentified insights into the complex EMT spectrum and its regulatory networks, as well as the contributions of epithelial-mesenchymal plasticity (EMP) in tumor heterogeneity in breast cancer.

In this review, the roles of RUNX1 in breast cancer are discussed in a context dependent manner based on its involvement in the development and progression of the disease. The association of RUNX1 with other types of cancer is also included to emphasize a wider and possibly a different angle of involvement of RUNX1 in cancer.

Collectively, PRADX/PRC2 complex activated the STAT3 pathway and energy metabolism in relation to mesenchymal GBM progression. Furthermore, our findings provided a novel therapeutic strategy targeting the energy metabolism activity of GBM.

Further analysis into DGE pathways combined with ChIP assays will help delineate mechanisms of action and identify additional potential targets for combination treatments. Orthotopic mouse models utilizing the metastasizing LM7 cell line with provide further information on the potential clinical utility of targeting the RUNX2-CBFβ interaction in OS.

SDM of CBFβ identified important residues for RUNX2 binding, which when targeted via a peptide resulted in a nearly 50% reduction in CBFβ and RUNX2 interaction. Ribosome footprinting combined with RNAseq and immunoprecipitation-mass spectrometry utilizing WT U2OS, CBFβ mutants and peptide-inhibited cells will provide further information on the translational role of CBFβ and potential therapeutic targets in OS.

Taking into consideration the identified cytogenetic abnormalities AML patients were classified by risk groups . Presence of the additional/secondary chromosomal aberrations in leukemic cells or new cells clones with multiple structural and numerical changes at AML relapse is the one sign of clonal evolution and progression of disease .