Biology subjects

Valk, P. J. M.

Publications and source records attributed to Valk, P. J. M..

4 recordsLinked to original sources

bioRxiv2023

The neuronal homeobox transcription factor HMX3 is a crucial vulnerability factor in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia

The KMT2A::MLLT3 fusion protein causes acute myeloid leukemia (AML) by activating the oncogenic transcription factor MECOM. However, MECOM expression occurs in only half of the KMT2A::MLLT3 cases. By integrating gene expression and enhancer activity data from patient cells, we identified neuronal homeobox transcription factor HMX3 as cell fate determining factor in MECOM-negative KMT2A::MLLT3 AML. HMX3 expression associated with younger age and KMT2A-rearranged leukemia in large AML cohorts (p<0.002). HMX3 was not expressed in other major genetic risk groups and healthy blood cells. Transcriptomic analyses revealed that HMX3 drives cancer-associated E2F, MYC and cell cycle gene programs. Ectopic HMX3 expression completely inhibited monocytic but not granulocytic colony formation of healthy CD34+ adult cells. Silencing of HMX3 in KMT2A::MLLT3 AML cell lines and patient cells resulted in cell cycle arrest, monocytic differentiation, and apoptosis. Thus, HMX3 is a leukemia-specific vulnerability that enhances proliferation and blocks differentiation of MECOM-negative KMT2A::MLLT3 leukemia.

cancer biology↗

bioRxiv2021

Cancer Prognosis According to Parthanatos Features

For nearly 50 years, translational research studies aimed at improving chemotherapy-induced killing of cancer cells have focused on the induction of apoptosis. Here we show that a PARP-1-mediated programmed cell death mechanism "parthanatos" is associated with the successful, front-line treatment of a common cancer. Peripheral blood mononuclear cells (PBMCs) from healthy human donors (10 of 10 tested), as well as primary cancer cells from approximately 50% of acute myeloid leukemia (AML) patients (n = 18 of 39 tested, French-American-British (FAB) subtypes M4 and M5) exhibited two distinctive features of parthanatos upon treatment with a front-line drug combination of cytarabine and an anthracycline. Statistically significant improvements in survival rates were observed in the parthanatos positive versus parthanatos negative AML patient groups (HR = 0.22 - 0.38, p = 0.002 - 0.05). Near-median expression of PARP1 mRNA was associated with a 50% longer survival time (HR = 0.66, p = 0.01), and the poly [ADP-ribose] polymerase (PARP) inhibitor Olaparib exhibited antagonistic activities against ara-C and idarubicin in primary blood monocytes from healthy donors as well as primary cancer isolates from ~50% of AML patients. Together these results suggest that PARP activity is a prognostic biomarker for AML subtypes M4 and M5 and support the relevance of parthanatos in curative chemotherapy of AML. In BriefMessikommer and co-workers report that PARP-1-mediated programmed cell death is associated with successful, front-line treatment of acute myeloid leukemia (AML). HighlightsO_LIThe first-line cancer drug cytarabine (ara-C) induces parthanatos or apoptosis, depending on the specific AML cell line being treated. C_LIO_LIOCI-AML3 cells undergo parthanatos or apoptosis, depending on the specific drug being added. C_LIO_LIThe presence of two parthanatos features in primary cancer cells from AML patients (n = 18 of 39 tested) having French-American-British (FAB) subclassifications M4 or M5 is associated with four-fold improved survival (HR = 0.23, p = 0.01) following curative chemotherapy with ara-C and an anthracycline. C_LIO_LIThe poly [ADP-ribose] polymerase (PARP) inhibitor Olaparib exhibits antagonistic activities against ara-C and idarubicin in primary blood monocytes from healthy donors as well as primary cancer isolates from ~50% of AML patients. C_LIO_LINear-median expression of PARP1 mRNA is associated with a 50% increase in survival time (HR = 0.66, p = 0.01) of AML patients following chemotherapy with ara-C and idarubicin. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=118 HEIGHT=200 SRC="FIGDIR/small/445484v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@af2a33org.highwire.dtl.DTLVardef@1fb8e1corg.highwire.dtl.DTLVardef@2eebf4org.highwire.dtl.DTLVardef@84eb8c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

TP53 abnormalities correlate with immune infiltration and are associated with response to flotetuzumab, an investigational immunotherapy, in acute myeloid leukemia

PurposeSomatic TP53 mutations and 17p deletions with genomic loss of TP53 occur in 37-46% of acute myeloid leukemia (AML) cases with adverse risk cytogenetics and are associated with primary induction failure (PIF), high risk of relapse and dismal prognosis. Herein, we aimed to characterize the immune landscape of TP53 mutated AML and to determine whether TP53 abnormalities identify a patient subgroup that may benefit from T-cell targeting immunotherapy approaches. Experimental DesignThe NanoString Pan-Cancer IO 360 assay was used for the immune transcriptomic analysis of 64 diagnostic bone marrow (BM) samples from adults with TP53 mutated AML (n=42) or TP53 wild type AML (n=22), and 35 BM samples from heavily pretreated patients with relapsed/refractory (R/R) AML (11 cases with TP53 mutations and/or 17p deletion with genomic loss of TP53) who received immunotherapy with flotetuzumab, an investigational CD123xCD3 bispecific DART(R) molecule (NCT02152956). In silico data series included The Cancer Genome Atlas (TCGA) cohort and a Dutch-Belgian Cooperative Trial Group for Hematology-Oncology (HOVON) cohort. ResultsAll TCGA cases with TP53 mutations (n=13) expressed higher levels of negative immune checkpoints, inflammatory chemokines, interferon (IFN)-{gamma}-inducible molecules, and had a higher tumor inflammation signature (TIS) score, compared with TCGA cases with other risk-defining molecular lesions. The comparison between TP53 mutated and TP53 wild type primary BM samples showed higher expression of IFNG, FoxP3, immune checkpoints and markers of exhaustion and senescence in the former cohort and allowed the computation of a 34-gene immune classifier prognostic for overall survival. In vitro modeling experiments with AML cell lines showed heightened expression of IFN-{gamma} and inflammation pathway genes in KG-1 cells (loss-of-function mutation of TP53) compared with Kasumi-1 cells (gain-of-function mutation of TP53). Finally, 5 out of 11 (45.5%) patients with R/R AML and TP53 abnormalities showed evidence of anti-leukemic activity of flotetuzumab immunotherapy and had higher TIS, FoxP3, CD8 T-cell abundance, inflammatory chemokine and PD1 gene expression scores at baseline compared with non-responders. ConclusionsThis study provides evidence for a correlation between IFN-{gamma}-dominant immune subtypes and TP53 abnormalities. The anti-leukemic activity with flotetuzumab encourages further study of this immunotherapeutic approach in this patient subgroup.

immunology↗

bioRxiv2017

Germline loss of MBD4 predisposes to leukaemia due to a mutagenic cascade driven by 5mC

Cytosine methylation is essential for normal mammalian development, yet also provides a major mutagenic stimulus. Methylcytosine (5mC) is prone to spontaneous deamination, which introduces cytosine to thymine transition mutations (C>T) upon replication1. Cells endure hundreds of 5mC deamination events each day and an intricate repair network is engaged to restrict this damage. Central to this network are the DNA glycosylases MBD42 and TDG3,4, which recognise T:G mispairing and initiate base excision repair (BER). Here we describe a novel cancer predisposition syndrome resulting from germline biallelic inactivation of MBD4 that leads to the development of acute myeloid leukaemia (AML). These leukaemias have an extremely high burden of C>T mutations, specifically in the context of methylated CG dinucleotides (CG>TG). This dependence on 5mC as a source of mutations may explain the remarkable observation that MBD4-deficient AMLs share a common set of driver mutations, including biallelic mutations in DNMT3A and hotspot mutations in IDH1/IDH2. By assessing serial samples taken over the course of treatment, we highlight a critical interaction with somatic mutations in DNMT3A that accelerates leukaemogenesis and accounts for the conserved path to AML. MBD4-deficiency was also detected, rarely, in sporadic cancers, which display the same mutational signature. Collectively these cancers provide a model of 5mC-dependent hypermutation and reveal factors that shape its mutagenic influence.

cancer biology↗