CBFA2T3 (CBFA2/RUNX1 Partner Transcriptional Co-Repressor 3)

Consequently, ectopic expression of BCL11A in LDB1-deficient proerythroblasts promotes their proliferation by rescuing them from ROS-mediated apoptosis. These findings highlight the essential role of LDB1 in fetal globin silencing during erythropoiesis.

LSPC-Cycle, FLT3-ITD and NUP98::KDM5A were considered independent prognostic factors in multivariate analysis. Findings indicate the prognostic relevance of cellular hierarchy and the importance of integrating hierarchy-specific molecular profiles for improved risk stratification and treatment formulation.

Using a doxycycline-inducible JAK2 knockout (KO) system, we validated JAK2 dependency in CBFA2T3::GLIS2 cell lines, observing impaired proliferation in vitro and in vivo and apoptosis induction in vitro. Both type I (ruxolitinib) and type II (CHZ868) JAK2 inhibitors showed selective in vitro activity in CBFA2T3::GLIS2-positive AML models...Both approaches converged on MAPK pathway activation as a resistance mechanism to ruxolitinib treatment. Combining ruxolitinib with MEK inhibitors showed a synergistic effect in cell lines and patient-derived xenograft (PDX) cells expressing the fusion and in vivo activity in a CBFA2T3::GLIS2 AML PDX, suggesting a potential approach to target this signaling circuitry in this poor outcome AML subtype.

Next-generation sequencing identified recurrent mutations in ASXL1 (50%), TET2, JAK2, and NRAS (each 25%). Clinically, this fusion strongly correlated with therapy-related myeloid neoplasms and demonstrated significantly worse survival outcomes compared to RUNX1::RUNX1T1 AML, highlighting its distinct clinicopathological features and adverse prognostic implications.

We analyzed the GBPs phenotype associated with LUAD progression and developed a risk score model for patient prognosis. This finding provided a reference model for clinically assessing patient prognosis, contributing to personalized treatment for LUAD patients.

Key issues ahead include identifying which genetic features truly affect outcomes, using this information to personalize therapy, predicting who will benefit from targeted drugs, and choosing the best markers to track disease response over time. Looking forward, collaborative efforts are urgently needed to validate pediatric-specific biomarkers, test novel drug combinations, and link genetic data to clinical outcomes to design trials and future treatment strategies.

This study elucidates the epigenetic mechanisms driving C/G+ pAML, showing how the fusion reshapes chromatin and DNA methylation landscapes by impacting the expression (and likely activity) of epigenetic modifiers like DNMT3B. Functionally, DNMT3B inhibition enhances apoptotic sensitivity to BCL2 blockade, indicating that targeting DNMT3B may overcome apoptotic resistance in C/G+ leukemic cells and offer a therapeutic strategy for this high-risk subtype.

In this Opinion, we highlight various investigative strategies, used in parallel by multiple independent research teams, that point to a specific dependence of CG2-expressing leukemias on the B cell leukemia/lymphoma-2 (BCL-2) family of antiapoptotic proteins. We propose that this intrinsic feature renders these leukemias particularly vulnerable to BCL-2 homology 3 (BH3) mimetics.

Transcriptomic analysis revealed major alterations in cell adhesion/migration pathways, cytokine-receptor interactions and DNA repair mechanisms. Collectively, these findings reveal stage-specific and compensatory roles for ARID1A and ARID1B in B cell development, uncover a mechanism by which SWI/SNF loss in early progenitors can drive transformation towards myeloid leukemia, and suggests context-dependent therapeutic vulnerabilities.

In contrast, aMKs partially sustain regulators of MK maturation but fail to complete differentiation due to repression of factors like NFE2, SPI1, GATA1 and LYL1. These insights may inform new strategies for targeting AMKL cell states.