bims-midomi 2025-04-06 papers

Leuk Lymphoma. 2025 Mar 31. 1-13

Mutation dynamics from diagnosis to relapse in acute myeloid leukemia with chromosomal 7 deletions.

Eitan Kugler, Enes Dasdemir, Alex Bataller, Bofei Wang, Courtney D DiNardo, Naval Daver, Musa Yilmaz, Nicholas J Short, Gautam Borthakur, Tapan M Kadia, Koji Sasaki, Danielle Hammond, Alexandre Bazinet, Ehsan Irajizad, Beenu Thakral, Sherry Pierce, Patrick Reville, Farhad Ravandi, Hussein A Abbas.

Monosomy 7 and 7q deletions (-7/del(7q)) are the most common adverse cytogenetic event in acute myeloid leukemia (AML), linked to high relapse rates. We analyzed 115 AML patients with -7/del(7q) who achieved remission after induction therapy to characterize the mutational landscape from diagnosis to relapse. Median overall survival (OS) was 10.4 months, with improved survival in patients without TP53 mutation (13.04 vs. 8.6 months) or complex karyotype (12.4 vs. 8.6 months). TP53 mutations were most frequent (67% of cases at diagnosis) and persisted in 97% of patients at relapse. At time of relapse, patients with TP53 mutations had fewer co-occurring mutations in ASXL1, RUNX1, NRAS, PTPN11 and SRSF2 compared to TP53 wild-type patients. Patients with mutated TP53 and co-mutation in NF1, BCORL1, GATA2, or RUNX1 had shorter relapse-free survival (2 vs. 5 months) and OS (7.2 vs. 10.4 months) than those with TP53 mutation alone. Allogeneic transplant improved OS significantly, regardless of TP53 status.

Keywords: Acute myeloid leukemia; chromosomal 7 deletions; mutational landscape

DOI: https://doi.org/10.1080/10428194.2025.2477723

Neoplasma. 2025 Mar 28. pii: 241120N481. [Epub ahead of print]

Inhibition of enzymatic activity of HRD1 results in death of cells derived from glioblastoma multiforme, neuroblastoma, and normal astrocytes.

Jaroslava Guzikova, Monika Liskova, Lubos Hudak, Maria Brodnanova, Andrea Evinova, Jozef Hatok, Peter Racay.

The aim of the present study was to examine the impact of LS-102, an inhibitor of enzymatic activity of HRD1 that is an essential E3 ubiquitin ligase of endoplasmic reticulum associated degradation (ERAD) on survival of the human cell lines derived from glioblastoma multiforme (GBM), neuroblastoma, and astrocytes. We have also examined molecular responses to HRD1 inhibition with a focus on proteins playing an essential role in unfolded protein response (UPR) and ERAD. In addition, activation of IRE1α documented by XBP1 splicing was investigated. Finally, we have examined the impact of LS-102 on p53 expression in GBM cells. Inhibition of HRD1 enzymatic activity results in cell death of all tested cells. With respect to GBM cells, U87 cells are more sensitive to LS-102 as T98G cells. Cells of cell lines derived from normal astrocytes K1884 exhibit the highest sensitivity to LS-102 among all cell types used in the study while NHA cells are the most resistant. Sensitivity of neuroblastoma SH-SY5Y cells to LS-102 is comparable to the sensitivity of U87 cells. In GBM cells, inhibition of HRD1 results in induction of the expression of proteins playing an essential role in UPR and ERAD (HRD1, SEL1L, and GRP78). XBP1 splicing induced by HRD1 inhibition was documented in T98G and K1884 cells. We did not observe induction of p53 expression in U87 cells. Since LS-102 induces cell death of normal astrocytes, it is not a candidate for the testing of its potential use as an antitumor treatment of GBM.

DOI: https://doi.org/10.4149/neo_2025_241120N481

bioRxiv. 2025 Mar 19. pii: 2025.03.18.643855. [Epub ahead of print]

GMCL1 Controls 53BP1 Stability and Modulates Paclitaxel Sensitivity in Cancer.

Yuki Kito, Tania J González-Robles, Sharon Kaisari, Juhee Pae, Sheena Faye Garcia, Juliana Ortiz-Pacheco, Beatrix Ueberheide, Ruth Lehmann, Antonio Marzio, Gergely Rona, Michele Pagano.

The Mitotic Surveillance Pathway (MSP) monitors the duration of M-phase. Prolonged mitosis, caused by spindle attachment defects or microtubule-targeting drugs such as the taxane paclitaxel, induces the formation of the ternary "mitotic stopwatch" complex consisting of 53BP1, USP28, and p53. This event protects p53 from degradation, resulting in cell cycle arrest or apoptosis in daughter cells. In paclitaxel-resistant cancers, cells bypass the MSP, enabling unchecked proliferation and survival, although the underlying mechanisms remain unknown. Here, we demonstrate that 53BP1 physically interacts with GMCL1 but not its paralog, GMCL2, and we mapped the interaction regions on both proteins. CRL3 GMCL1 functions as a ubiquitin ligase that targets 53BP1 for degradation during M phase, impacting p53 levels in daughter cells. High GMCL1 expression significantly correlates with resistance to paclitaxel in cancer cell lines with wild-type p53, including endometrial, breast, and upper aerodigestive tract cancer cells. Loss of GMCL1 restores paclitaxel sensitivity in p53 expressing cells but not in p53 deficient cells. We propose that in cancers with high GMCL1 levels, the CRL3 GMCL1 -mediated degradation of 53BP1 prevents the formation of the mitotic stopwatch complex, leading to p53 degradation and sustained proliferation. Finally, our results indicate that GMCL1 inhibition represents a novel strategy to restore taxane sensitivity in resistant cancers.

DOI: https://doi.org/10.1101/2025.03.18.643855

Blood. 2025 Mar 31. pii: blood.2024027117. [Epub ahead of print]

Efficacy of a Novel BCL-xL Degrader, DT2216, in Preclinical Models of JAK2-mutated Post-MPN AML.

Acute myeloid leukemia (AML) that evolves from myeloproliferative neoplasm (MPN) is known as post-MPN AML. Current treatments don't significantly extend survival beyond 12 months. BCL-xL has been found to be overexpressed in leucocytes from MPN patients, making it a potential therapeutic target. We investigated the role of BCL-xL in post-MPN AML and tested the efficacy of DT2216, a platelet-sparing BCL-xL proteolysis-targeting chimera (PROTAC), in preclinical models of post-MPN AML. We found that BCL2L1, the gene encoding BCL-xL, is expressed at higher levels in post-MPN AML patients compared to those with de novo AML. Single-cell multi-omics analysis revealed that leukemia cells harboring both MPN-driver and TP53 mutations exhibited higher BCL2L1 expression, elevated scores for leukemia stem cell, megakaryocyte development, and erythroid progenitor than wild-type cells. BH3 profiling confirmed a strong dependence on BCL-xL in post-MPN AML cells. DT2216 alone, or in combination with standard AML/MPN therapies, effectively degraded BCL-xL, reduced the apoptotic threshold, and induced apoptosis in post-MPN AML cells. DT2216 effectively eliminated viable cells in JAK2-mutant AML cell lines, induced pluripotent stem cell-derived hematopoietic progenitor cells (iPSC-HPCs), primary samples, and reduced tumor burden in cell line-derived xenograft model in vivo by degrading BCL-xL. DT2216, either as a single agent or in combination with azacytidine, effectively inhibited the clonogenic potential of CD34+ leukemia cells from post-MPN AML patients. In summary, our data indicate that the survival of post-MPN AML is BCL-xL dependent, and DT2216 may offer therapeutic advantage in this high-risk leukemia subset with limited treatment options.

DOI: https://doi.org/10.1182/blood.2024027117