Biology subjects

Lasho, T.

Publications and source records attributed to Lasho, T..

3 recordsLinked to original sources

bioRxiv2026

APR-246 and DNA polymerase theta inhibitor Novobiocinsynergize to eliminate TP53 mutant AML cells

Patients with TP53-mutant myelodysplasic syndromes (MDS) and acute myeloid leukemia (AML) are usually elderly and frail with highly resistant malignant clones and a median survival of less than one year. The molecule APR-246 targets mutant p53 but also perturbs redox homeostasis. APR-246 showed favorable safety in a phase 3 trial in TP53 mutant MDS/AML but did not meet efficacy endpoints in combination with azacitidine (AZA), highlighting the need for more effective combination strategies. Conversion of APR-246 to the active compound MQ releases formaldehyde which generates DNA-protein crosslinks. AML cells depend on DNA polymerase theta (Pol[O]) to repair such lesions and Pol[O] protects cells from ferroptosis. Using a panel of isogenic MOLM13 AML cell lines each carrying a common TP53 variant, we show that the Pol[O] inhibitor Novobiocin (NVB) synergizes with APR-246 to induce AML cell death. We demonstrate strong synergy with this combination in all TP53 mutant cell lines and to a lesser extent in the TP53 wildtype and null cells, indicating both p53-dependent and p53-independent mechanisms behind the synergy. APR-246 provides selectivity for TP53-mutated cells while NVB enhances p53-independent apoptosis and p53-dependent ferroptosis. Levels of ferroptosis induction correlate with the observed synergy in TP53-mutant and WT cells. Combination of APR-246 and NVB induces potent in vitro growth inhibition of primary TP53-mutated AML/CMML patient samples, with significant activity achieved at low micromolar or nanomolar concentrations of APR-246. Our findings hold promise for combination of APR-246 and NVB as a new therapeutic strategy tailored for TP53-mutated AML patients with high efficacy and low toxicity.

cancer biology↗

bioRxiv2022

Genomic and transcriptional profiling stratifies VQ myeloma lines into two clusters with distinct risk signatures and drug responses

Multiple myeloma (MM) is a cancer of malignant plasma cells in the bone marrow and extramedullary sites. We previously characterized a VQ model for human high-risk MM. Different VQ lines display distinct disease phenotypes and survivals, suggesting significant intra-model variation. Here, we use whole exome sequencing and copy number variation (CNV) analysis coupled with RNA-Seq to stratify VQ lines into corresponding clusters: Cluster I VQ cells carried recurrent amplification of chromosome (chr) 3 and displayed upregulation of growth pathways and high-risk myeloma gene signatures, whereas Cluster II cells had monosomy chr5 and overexpressed genes and pathways associated with positive response to bortezomib (Btz) treatment in human MM patients. Consistently, in sharp contrast to Cluster II VQ cells that showed short-term response to Btz, Cluster I VQ cells were de novo resistant to Btz in vivo. Our study highlights Cluster I VQ lines as highly representative of human high-risk MM subset.

cancer biology↗

bioRxiv2019

RAS mutations drive proliferative chronic myelomonocytic leukemia via activation of a novel KMT2A-PLK1 axis

ABSTRACTChronic myelomonocytic leukemia (CMML) is an aggressive hematological malignancy with limited treatment options. Whole exome (WES) and targeted sequencing of several independent cohorts of CMML patients, comparing dysplastic (dCMML) to proliferative (pCMML) CMML, as well as paired chronic phase disease and acute leukemic transformation (LT), associate acquisition of oncogenic RAS pathway mutations, the most common being NRASG12D, with aggressive disease and with disease progression. Using patient derived progenitor colony assays and a NRASG12D-Vav-Cre mouse model, we further demonstrate the role of mutant RAS signaling in driving and maintaining pCMML phenotype. RNA-sequencing links RAS pathway mutations with an increased expression of genes encoding the mitotic checkpoint kinases PLK1 and WEE1. Further, we dmeoinstrated that non-mutated lysine methyltransferase KMT2A (MLL1) acts as mediator of NRAS-induced PLK1 and WEE1 expression. Finally, we demonstrate the translational value of our findings by showing that pharmacological PLK1 inhibition decreases monocytosis and hepatosplenomegaly while improving hematopoiesis in RAS mutant patient-derived xenografts. Hence, we define severe CMML as oncogenic RAS pathway-enriched malignancies, with a unique gene expression profile regulated by KMT2A, amenable to therapeutic intervention.

cancer biology↗