In acute myeloid leukemia (AML), the restoration of p53 activity through MDM2 inhibition proved efficacy in combinatorial therapies. WIP1, encoded from
, is a negative regulator of p53. We evaluated
...expression and explored the therapeutic efficacy of WIP1 inhibitor (WIP1i) GSK2830371, in association with the MDM2 inhibitor Nutlin-3a (Nut-3a) in AML cell lines and primary samples.
transcript levels were higher in young patients compared with older ones and in core-binding-factor AML compared with other cytogenetic subgroups. In contrast, its expression was reduced in
-mutated (mut, irrespective of
-ITD status) or
-mut cases compared with wild-type (wt) ones. Either Nut-3a, and moderately WIP1i, as single agent decreased cell viability of
-wt cells (MV-4-11, MOLM-13, OCI-AML3) in a time/dosage-dependent manner, but not of
-mut cells (HEL, KASUMI-1, NOMO-1). The drug combination synergistically reduced viability and induced apoptosis in
-wt AML cell line and primary cells, but not in
-mut cells. Gene expression and immunoblotting analyses showed increased p53, MDM2 and p21 levels in treated
-wt cells and highlighted the enrichment of MYC, PI3K-AKT-mTOR and inflammation-related signatures upon WIP1i, Nut-3a and their combination, respectively, in the MV-4-11
-wt model. This study demonstrated that WIP1 is a promising therapeutic target to enhance Nut-3a efficacy in
-wt AML.
The introduction of target molecules and immunological therapies is changing the treatment landscape of acute myeloid leukemia (AML).
We recapitulate the biological therapies that can be employed in ...the treatment of elderly patients with AML. Alongside small molecules inhibitors that target specific gene mutations, antibodies, tumor microenvironment modulators, and cellular therapies are being developed for the cure of the disease. Here, we report the biological activities, the efficacy and toxicities of humanized antibodies and antibody-drug conjugates that targets surface antigens as CD33 (gemtuzumab ozogamicine) or CD123 (pivekimab sunirine). We further explore mechanisms and effectiveness of medications that modify the microenvironment, such as glasdegib, or that harness the immune system against leukemia, such as CD47 antibody magrolimab, PD1/PDL1 inhibitors pembrolizumab and nivolumab, TIM3 inhibitor sabatolimab, T-cell and NK-cell engagers. Cellular therapies are considered, even if a large trial is still pending for the feasibility of the approach. In this scenario, a brief overview of the mechanism of action of target agents is provided, particularly with respect to their biological mechanisms.
Overall, this therapeutic armamentarium will constitute the basis for multimodal and personalized combinations that, in the idea of precision medicine, will enormously benefit elderly AML patients.
Introduction: Venetoclax (VEN), a BCL-2 inhibitor, effectively induces apoptosis in acute myeloid leukemia (AML) cells. Resistance to VEN in the treatment of AML can occur through various mechanisms. ...Some of the identified resistance mechanisms include: expansion or gain of clones with activation of the receptor tyrosine kinase (RTK) pathway; disruption of TP53 function, a tumor suppressor gene known to play a critical role in cell cycle regulation and apoptosis; selection of AML populations with monocytic differentiation, possibly altering cellular characteristics and response to treatment; overexpression of the MCL1 gene, which encodes for a protein that can counteract the pro-apoptotic effects of venetoclax; switch to lipid metabolism, an adaptive response by leukemia cells that may confer resistance to venetoclax; mutations in BCL-2 and BAX genes, which could affect the activity of these key regulators of apoptosis. While these mechanisms have been extensively studied, the role of rearrangements, often combined with genomic events, has not been fully explored. The INTHEMA protocol (NCT04298892) aimed to identify new VEN resistance mechanisms in patients with relapsed/refractory AML treated with VEN in combination with hypomethylating agents and to provide addressable molecular pathways useful for restoring drug sensitivity or offer novel therapeutic opportunities. Methods: Informed consent was obtained from 21 consecutive patients. Samples were collected from these patients with relapse or refractory disease after VEN + hypomethylating agent treatment. TruSight RNA Pan-Cancer analysis was performed to investigate fusion genes (using capture technology covering 1385 genes), RNA expression, and expressed mutations for each sample. Results: Among the 21 patients, 17 (81%) showed at least one putative mechanism of VEN resistance (as illustrated in the figure). These mechanisms included co-occurring mutations and genomic rearrangements. RTK mutations were found in 14 patients (67%), with specific mutations observed in NRAS, PTPN11, CBL, FLT3, JAK2, cKIT, EPHB6, FGFR and PDGFRb. One patient had a BAX mutation (p.G67R; BH3 domain), three patients exhibited a switch to a monocytic phenotype, and two patients had marker chromosomes. Gene fusions were identified in eight patients (38%): in particular, we discovered a cryptic rearrangement of MECOM (TBL1XR1-MECOM and ETV6_MECOM) in 2 patients, a novel BCL11B fusion ( BCL11B-GSDMC), a CCND2-ETV6 BIRC6-LTBP1, the reciprocal NUP98-NSD1, the canonical CBFB-MYH11 and additional transcripts with less defined roles ( PSPC1-ZMYM2, PER1-DDX5, ELL-SUGP2). Interestingly, most of the genes involved in traslocations, with a potential driver role in therapy resistance ( MECOM, ETV6, CCND2, BCL11B, NUP98) also showed high expression levels in patients harboring the traslocation. Unsupervised clustering of RNA expression data revealed two main patient groups. The first group (24%) demonstrated an “activating-like” signature, characterized by overexpression of CSF3R and IKZF, suggesting a potential target for tyrosine kinase inhibitors. The second group exhibited a “self-renewal like” signature, suggesting a possible benefit from histone deacetylase inhibitors, as previously published. Patients with gene fusions were predominantly clustered within the “self-renewal like” group, particularly in a subgroup (subgroup 4) showing overexpression of HOXA genes. Conclusions: Through deep transcriptomic characterization combined with conventional diagnostics, this analysis uncovered novel mechanisms of VEN resistance while confirming established ones. The distinct gene expression patterns may help tailor targeted therapies, with patients showing the “activating-like” signature potentially benefiting from tyrosine kinase inhibitors and those with the “self-renewal like” signature possibly responding well to histone deacetylase inhibitors. Furthermore, HOXA gene overexpression presents an exciting therapeutic opportunity for selected patients. Further research and clinical validation are needed to translate these findings into actionable clinical strategies.
Background: Myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) are occasionally observed in association with lymphoid tumors. Most cases of myeloid disorders detected in patients with ...lymphoid tumors are attributed to chemotherapy, however, there is a subset of patients who receive a contemporary diagnosis of myeloid and lymphoid disease, and it is well known that, even in patients who were exposed to chemotherapy, the myeloid disease may both arise from clonal hematopoiesis substrate or harbor chemotherapy signature (Diamond, Blood 2023). Biological differences justified by the ontogenesis of the myeloid disease may justify prognosis and suggest appropriate intervention methods. Methods: We searched our patient database for AML and MDS which were diagnosed together with lymphoid diseases. Data was collected under the study NCT04298892, after approval of the ethical committee. Statistics were performed with Kaplan-Meyer estimation. Nonparametric tests were used as appropriate. Results: Out of 164 patients who were referred to our service from May 2021 to Jul 2023 for MDS or AML, 11 patients were diagnosed with AML or MDS together with a concomitant or previous lymphoid disease. In this population, the median age at AML or MDS diagnosis was 67 (range 58 - 82); 9/11 (82%) patients were male. Four out of 11 (36%) patients were diagnosed with AML, 7/11 with MDS (6 with blast < 5% and 1 with blast ≥ 5%). The diagnosis of myeloid and lymphoid diseases was concomitant in 2 patients (18%) and sequential in 9 patients (82%). The lymphoid diseases were smoldering multiple myeloma (3/11, 27%), multiple myeloma (5/11, 45%), diffuse large B-cell lymphoma (1/11, 9%), mantle cell lymphoma (1/11, 9%), marginal zone lymphoma (1/11, 9%). Eight out of 11 patients (73%) with lymphoid and myeloid disease had a history of chemotherapy before the diagnosis of MDS or AML; 5 patients (45%) were exposed to high-dose alkylating agents, 2 (18%) low-dose alkylating agents, 2 (18%) anthracyclines. Interestingly, 7 patients (64%) were diagnosed while they were receiving lenalidomide after a median exposure to lenalidomide of 8.8 months (4.9 - 30.73). In the 9 patients with consecutive lymphoid and myeloid disease diagnosis, AML or MDS were diagnosed after a median of 23 months (range 8 - 76; history of patients is plotted in figure 1). Regarding the AML or MDS, 3/11 patients (27%) had complex karyotype of which 1 had t(3;21)(q26;q22) RUNX1/MECOM rearrangement, 2/11 had TP53 mutation (both also had complex karyotype). The remaining patients mainly harbored methylation or splicing mutations and normal karyotype or karyotype single non-high-risk alterations. When compared, patients with complex alterations had similar times of onset from their first tumor and baseline characteristics; those patients however had an increased risk of death. Conclusions: The incidence of AML or MDS associated with lymphoid disease is low.Furthermore, the population is remarkably heterogeneous. The characteristics and the timing of onset of the disease account for different ontogenesis; a portion of the patient has a disease that harbors complex alterations, while the most frequent origin of AML and MDS can be researched in pre-existing or contemporary hematopoietic clones, that overall account for a whole bone-marrow disease. The relation between chemotherapy exposition and the biology of the AML or MDS is not univocal. This difference could be therapeutically relevant.
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