Molecular characterization and prognosis of mutant TP53 acute myeloid leukemia and myelodysplastic syndrome with excess blasts.

INTRODUCTION: Myeloid tumors typically harbor TP53 mutations, which are linked to a dismal prognosis. There are fewer studies on whether TP53-mutated acute myeloid leukemia (AML) and myelodysplastic syndrome with excess blasts (MDS-EB) differ in molecular characteristics and should be considered as separate entities. METHODS: Between January 2016 and December 2021, a retrospective analysis was done on a total of 73 newly diagnosed AML patients and 61 MDS-EB patients from the first affiliated hospital of Soochow University. We described a survival profile and a thorough characterization of newly found TP53-mutant AML and MDS-EB and investigated the relationship between these characteristics and overall survival (OS). RESULTS: 38 (31.1%) were mono-allelic, and 84 (68.9%) were bi-allelic. There is no significant difference between TP53-mutated AML and MDS-EB (median OS 12.9 verse 14.4 months; p = .558). Better overall survival was linked to mono-allelic TP53 than bi-allelic TP53(HR = 3.030, CI:1.714-5.354, p < .001). However, the number of TP53 mutations and comutations were not significantly associated with OS. TP53 variant allele frequency cutoff of 50% is significant correlation with OS (HR: 2.177, 95% CI: 1.142-4.148; p = .0063). CONCLUSION: Our data revealed that allele status and allogeneic hematopoietic stem cell transplant independently affect the prognostic of AML and MDS-EB patients, with a concordance of molecular features and survival between these two disease entities. Our analysis favors considering TP53-mutated AML/MDS-EB as a distinct disorder.

Identification of a venetoclax-resistance prognostic signature base on 6-senescence genes and its clinical significance for acute myeloid leukemia.

Background: Satisfactory responses can be obtained for acute myeloid leukemia (AML) treated by Venetoclax (VEN)-based therapy. However, there are still quite a few AML patients (AMLs) resistant to VEN, and it is critical to understand whether VEN-resistance is regulated by senescence. Methods: Here, we established and validated a signature for predicting AML prognosis based on VEN resistance-related senescence genes (VRSGs). In this study, 51 senescence genes were identified with VEN-resistance in AML. Using LASSO algorithms and multiple AML cohorts, a VEN-resistance senescence prognostic model (VRSP-M) was developed and validated based on 6-senescence genes. Results: According to the median score of the signature, AMLs were classified into two subtypes. A worse prognosis and more adverse features occurred in the high-risk subtype, including older patients, non-de novo AML, poor cytogenetics, adverse risk of European LeukemiaNet (ELN) 2017 recommendation, and TP53 mutation. Patients in the high-risk subtype were mainly involved in monocyte differentiation, senescence, NADPH oxidases, and PD1 signaling pathway. The model's risk score was significantly associated with VEN-resistance, immune features, and immunotherapy response in AML. In vitro, the IC50 values of ABT-199 (VEN) rose progressively with increasing expression of G6PD and BAG3 in AML cell lines. Conclusions: The 6-senescence genes prognostic model has significant meaning for the prediction of VEN-resistance, guiding personalized molecularly targeted therapies, and improving AML prognosis.

Case report: Identification of a novel HNRNPC::RARG fusion in acute promyelocytic leukemia lacking RARA rearrangement.

Acute promyelocytic leukemia (APL) is a special subtype of acute myeloid leukemia (AML), 95% patients have PML-RARA fusion gene as a result of a reciprocal chromosomal translocation t(15;17)(q22; q21). The retinoic acid receptors (RARs) belong to nuclear hormone receptors which modulate the transcription of DNA elements. RARs have three isoforms: retinoic acid receptor alpha (RARA), retinoic acid receptor beta (RARB) and retinoic acid receptor gamma (RARG). In this study, we describe the experimental results of a case with HNRNPC::RARG gene transcript with morphologic and immunophenotypic features similar to APL, including bone marrow morphology and immunophenotype, which showed poor response to ATO and chemotherapy. Then the patient achieved remission under the combination of BCL-2 inhibitor (Venetoclax) and standard 7 + 3 chemotherapy in second induction chemotherapy. The treatment in this case demonstrated effective response to Venetoclax, which suggested its possible role for the patient with acute promyelocytic-like leukemias (APLL).