Peter J M Valk's research while affiliated with Erasmus MC and other places
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Publications (263)
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 dete...
Objectives
Acquired missense mutations in the BCR::ABL1 kinase domain (KD) may cause tyrosine kinase inhibitor (TKI) treatment failure. Based on mutation‐specific in vitro derived IC50‐values, alternative TKI may be selected. We assessed clinical practice of BCR::ABL1 KD mutation testing, clinical response in relation to IC50‐values, and clinical o...
It remains challenging in chronic lymphocytic leukemia (CLL) to distinguish between patients with favorable and unfavorable time-to-first treatment (TTFT). Additionally, the downstream protein correlates of well-known molecular features of CLL are not always clear. To address this, we selected 40 CLL patients with TTFT ≤24 months and compared their...
With the availability of effective targeted agents, significant changes have occurred in the management of patients with acute myeloid leukemia (AML) over the past several years, particularly for those considered unfit for intensive chemotherapy. While testing for measurable residual disease (MRD) is now routinely performed in patients treated with...
Previous chemotherapy research has focused almost exclusively on apoptosis. Here, a standard frontline drug combination of cytarabine and idarubicin induces distinct features of caspase-independent, poly(ADP-ribose) polymerase 1 (PARP-1)-mediated programmed cell death "parthanatos" in acute myeloid leukemia (AML) cell lines (n = 3/10 tested), perip...
Treatment choice according to the individual conditions remains challenging, particularly in older patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). The impact of performance status, comorbidities, and physical functioning on survival is not well defined for patients treated with hypomethylating agents. Here w...
Purpose:
The applicability of FLT3-internal tandem duplications (FLT3-ITD) for assessing measurable residual disease (MRD) in acute myeloid leukemia (AML) in complete remission (CR) has been hampered by patient-specific duplications and potential instability of FLT3-ITD during relapse. Here, we comprehensively investigated the impact of next-gener...
We describe a patient with congenital neutropenia (CN) with a homozygous germline mutation in the colony-stimulating factor 3 receptor gene (CSF3R). The patient's bone marrow shows lagging neutrophil development with subtle left shift and unresponsiveness to CSF3 in in vitro colony assays. This patient illustrates that the di-proline hinge motif in...
Context:
Acute myeloid leukemia (AML) is a heterogeneous disease, which can be clinically classified in de novo AML or secondary AML (sAML) and separate from therapy-related AML. Secondary AML evolves from an antecedent hematological disorder, whereas de novo AML arises in absence of any prior hematological disease or leukemogenic treatment. A bro...
Substantial heterogeneity within mutant TP53 AML and MDS-EB precludes the exact assessment of prognostic impact for individual patients. Here we performed in-depth clinical and molecular analysis of mutant TP53 AML and MDS-EB to dissect the molecular characteristics in detail and determine its impact on survival. We performed next-generation sequen...
Clofarabine is an active antileukemic drug for subgroups of patients with acute myeloid leukemia (AML). Multi-state models can provide additional insights to supplement the original intention-to-treat analysis of randomized controlled trials (RCT). We re-analyzed the HOVON102/SAKK30/09 phase III RCT for newly diagnosed AML patients, which randomize...
Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML) that is used for prognostic, predictive, monitoring, and efficacy-response assessments. The European LeukemiaNet (ELN) MRD working party evaluates standardization and harmonization of MRD in an ongoing manner and has updated the 2018 ELN MRD recommendations...
Initial induction chemotherapy to eradicate the bulk of acute myeloid leukemia (AML) cells results in complete remission (CR) in the majority of patients. However, leukemic cells persisting in the bone marrow below the morphologic threshold remain unaffected and have the potential to proliferate and re-emerge as AML relapse. Detection of minimal/me...
Splicing factor (SF) mutations are important contributors to the pathogenesis of hematological malignancies; however, their relevance in risk classification of acute myeloid leukemia (AML) warrants further investigation. To gain more insight into the characteristics of patients with AML carrying SF mutations, we studied their association with clini...
Clonal hematopoiesis is a prevalent age-related condition associated with a greatly increased risk of hematologic disease; mutations in DNA methyltransferase 3A (DNMT3A) are the most common driver of this state. DNMT3A variants occur across the gene with some particularly associated with malignancy, but the functional relevance and mechanisms of pa...
Biallelic mutations of the CEBPA gene (CEBPAbi) define a distinct entity associated with favorable prognosis, however the role of monoallelic mutations (CEBPAsm) is poorly understood. We retrospectively analyzed 4708 adult AML patients recruited into Study Alliance Leukemia trials to investigate the prognostic impact of CEBPAsm. CEBPA mutations wer...
Incidence, molecular presentation and outcome of acute myeloid leukaemia (AML) is influenced by sex, but little attention has been directed at untangling sex‐related molecular and phenotypic differences between female and male patients. While increased incidence and poor risk is generally associated with a male phenotype, the poor prognostic FLT3 i...
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 cel...
Measurable (previously minimal) residual disease (MRD) detection in acute myeloid leukemia (AML) has progressed beyond being a recognized strong prognostic factor. MRD-risk stratification is now incorporated into many treatment schedules and there is ongoing evaluation of MRD-directed therapy. Evolving assay technology such as next-generation seque...
Recurrent somatic internal tandem duplications (ITD) in the FMS‐like tyrosine kinase 3 (FLT3) gene characterise approximately one third of patients with acute myeloid leukaemia (AML), and FLT3‐ITD mutation status guides risk‐adapted treatment strategies. The aim of this work was to characterise FLT3‐ITD variant distribution in relation to molecular...
Key Points
Human inv(16) AML cells express CSF-1R and are exposed to CSF-1 in vivo. Inhibition of CSF-1R signaling reduces viability of inv(16) AML cells in vitro and in therapeutic settings in humanized mice in vivo.
Lenalidomide, an antineoplastic and immunomodulatory drug, has therapeutic activity in acute myeloid leukemia (AML), but definitive studies about its therapeutic utility have been lacking. In a phase 3 study, we compared 2 induction regimens in newly diagnosed patients age 18 to 65 years with AML: idarubicine-cytarabine (cycle 1) and daunorubicin a...
Acute myeloid leukemia (AML) is caused by genetic aberrations that also govern the prognosis of patients and guide risk-adapted and targeted therapy. Genetic aberrations in AML are structurally diverse and currently detected by different diagnostic assays. This study sought to establish whole transcriptome RNA sequencing as single, comprehensive, a...
Cytarabine and daunorubicin are old drugs commonly used in the treatment of acute myeloid leukaemia (AML). Refractory or relapsed disease because of chemotherapy resistance is a major issue. microRNAs (miRNAs) were incriminated in resistance. This study aimed to identify miRNAs involved in chemoresistance in AML patients and to define their target...
Molecular monitoring of the BCR-ABL1 transcript for patients with chronic phase chronic myeloid leukemia (CML) has become increasingly demanding. Real-time quantitative PCR (qPCR) is the routinely used method, but has limitations in quantification accuracy due to its inherent technical variation. Treatment recommendations rely on specific BCR-ABL1...
Acquired aplastic anemia and severe congenital neutropenia (SCN) are bone marrow (BM)
failure syndromes of different origin, however, they share a common risk for secondary
leukemic transformation. Here, we present a patient with severe aplastic anemia (SAA)
evolving to secondary chronic neutrophilic leukemia (CNL; SAA-CNL). We show that SAACNL
sha...
Introduction: Somatic TP53 mutations and deletions of 17p, to which TP53 is mapped, (TP53mut) occur in 8-10% of de novo Acute myeloid leukemia (AML) and in up to 37-46% of patients (pts) with adverse-risk cytogenetics and treatment-related myeloid neoplasms and confer a poor prognosis. In addition to its well-characterized function as a tumor suppr...
Somatic TP53 mutations and 17p deletions with genomic loss of TP53 occur in 37% to 46% of acute myeloid leukemia (AML) with adverse-risk cytogenetics and correlate with primary induction failure, high risk of relapse, and dismal prognosis. Herein, we aimed to characterize the immune landscape of TP53-mutated AML and determine whether TP53 abnormali...
Nucleosides and their analogues constitute an essential family of anticancer drugs. DNA has been the presumptive target of the front-line prodrug for acute myeloid leukemia (AML), cytarabine (ara-C), since the 1980s. Here, the biomolecular targeting of ara-C was evaluated in primary white blood cells using the ara-C mimic “AzC” and azide–alkyne “cl...
The treatment of older, unfit patients with acute myeloid leukemia (AML) is challenging. Based on preclinical data of Bruton tyrosine kinase expression/phosphorylation and ibrutinib cytotoxicity in AML blasts, we conducted a randomized phase 2 multicenter study to assess the tolerability and efficacy of the addition of ibrutinib to 10-day decitabin...
Background: Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous disease. mutations and 17p () deletions occur in 37-46% of 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 determine whether abnormalities identify a...
Abstract
Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous hematological malignancy. Although immunotherapy may be an attractive modality to exploit in patients with AML, the ability to predict the groups of patients and the types of cancer that will respond to immune targeting remains limited. This study dissected the comp...
Acute myeloid leukemia (AML) with inv(3)/t(3;3)(q21q26) is a distinct WHO recognized entity, characterized by its aggressive course and poor prognosis. In this subtype of AML, the translocation of a GATA2 enhancer (3q21) to MECOM (3q26) results in overexpression of the MECOM isoform EVI1 and monoallelic expression of GATA2 from the unaffected allel...
Acute myeloid leukemia (AML) carries a 10–100 fold lower mutational burden than other neoplastic entities. Mechanistic explanations for why a low number of mutations suffice to induce leukemogenesis are therefore required. Here we demonstrate that transgenic overexpression of the wild type sphingosine-1-phosphate receptor 3 (S1P3) in murine hematop...
Purpose
Somatic 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...
Calcitonin receptor-like (CALCRL) is a G-protein-coupled neuropeptide receptor involved in the regulation of blood pressure, angiogenesis, cell proliferation, and apoptosis, and is currently emerging as a novel target for the treatment of migraine. This study characterizes the role of CALCRL in acute myeloid leukemia (AML). We analyzed CALCRL expre...
Current risk algorithms are primarily based on pre-treatment factors and imperfectly predict outcome in acute myeloid leukemia (AML). We introduce and validate a post-treatment approach of leukemic stem cell (LSC) assessment for prediction of outcome. LSC containing CD34+CD38− fractions were measured using flow cytometry in an add-on study of the H...
In acute myeloid leukemia (AML), acquired genetic aberrations carry prognostic implications and guide therapeutic decisions. Clinical algorithms have been improved by the incorporation of novel aberrations. Here, we report the presence and functional characterization of mutations in the transcription factor NFE2 in patients with AML and in a patien...
Acute myeloid leukemia with t(8;21)(q22;q22) is characterized by considerable clinical and biological heterogeneity leading to relapse in up to 40% of patients. We sequenced coding regions or hotspot areas of 66 recurrently mutated genes in a cohort of 331 t(8;21) patients. At least 1 mutation, in addition to t(8;21), was identified in 95%, with a...
Introduction
Acute myeloid leukemia (AML) is characterized by uncontrolled proliferation of malignant myeloid progenitor cells in the bone marrow that are arrested in differentiation. In AML, genetic aberrations often involve the same genes and play an important role in risk assessment and treatment of AML. In the WHO classification 2016 (Arber et...
Acute myeloid leukemia (AML) is a heterogeneous disease with a great variety of somatic driver mutations. Each AML carries specific (combinations of) acquired mutations, which enables minimal residual disease (MRD) detection in virtually every patient with next-generation sequencing (NGS). In recent years there has been an increasing interest to co...
The tendency of 5-methylcytosine (5mC) to undergo spontaneous deamination has had a major role in shaping the human genome, and this methylation damage remains the primary source of somatic mutations that accumulate with age. How 5mC deamination contributes to cancer risk in different tissues remains unclear. Genomic profiling of 3 early-onset acut...
Spontaneous methylcytosine (5mC) deamination is a common source of cytosine to thymine (C>T) mutations. These mutations accumulate over time, serving as a “molecular clock” that tracks cellular age. is a thymine glycosylase that recognises sites of 5mC deamination and initiates base excision repair.
Three patients (of whom 2 are siblings) with germ...
This corrects the article DOI: 10.1038/ncomms1681.
Background
Patients with acute myeloid leukemia (AML) often reach complete remission, but relapse rates remain high. Next-generation sequencing enables the detection of molecular minimal residual disease in virtually every patient, but its clinical value for the prediction of relapse has yet to be established.
Methods
We conducted a study involvin...
Immunological aging remodels the immune system at several levels. This has been documented in particular for the T-cell receptor (TCR)αβ+ T-cell compartment, showing reduced naive T-cell outputs and an accumulation of terminally differentiated clonally expanding effector T-cells, leading to increased proneness to autoimmunity and cancer development...
Objectives:
The monitoring of response in chronic myeloid leukemia (CML) is of great importance to identify patients failing their treatment in order to adjust TKI choice and thereby prevent progression to advanced stage disease. Cytogenetic monitoring has a lower sensitivity, is expensive, and requires invasive bone marrow sampling. Nevertheless,...
Introduction:
Although the majority of Acute Myeloid Leukemia (AML) patients achieve a complete morphological remission (CR) after induction therapy, relapse rates remain high. Molecular Minimal Residual Disease (MRD) detection by PCR-based technologies has been shown to improve relapse prediction but has been restricted to specific genetically-def...
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 replication ¹ . Cells endure hundreds of 5mC deamination events each day and an intricate repair network is e...
Overexpression of the BRE (Brain and Reproductive organ-Expressed) gene defines a distinct pediatric and adult acute myeloid leukemia (AML) subgroup. Here we identify a promoter enriched for active chromatin marks in BRE intron 4 causing strong biallelic expression of a previously unknown C-terminal BRE transcript. This transcript starts with BRE i...
Clofarabine has demonstrated antileukemic activity in acute myeloid leukemia (AML) but has yet to be critically evaluated in younger adults in the frontline with standard chemotherapy. We compared 2 induction regimens in newly diagnosed patients ages 18 to 65 with acute myeloid leukemia (AML)/high-risk myelodysplastic syndromes, that is, idarubicin...
Refractoriness to induction chemotherapy and relapse after achievement of remission are the main obstacles to cure in acute myeloid leukaemia (AML). After standard induction chemotherapy, patients are assigned to different post-remission strategies on the basis of cytogenetic and molecular abnormalities that broadly define adverse, intermediate and...
Background
Acute myeloid leukemia (AML) is caused by cooperating oncogenic driver mutations that induce uncontrolled proliferation in combination with maturation arrest in myeloid precursor cells. The majority of oncogenic drivers are somatically acquired. Recurrent genetic lesions are used for molecular classification and prognosis of AML. In addi...
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Unfortunately, a significant proportion of patients relapse after responding to initial treatment reflecting our poor understanding of the mechanisms mediating therapy resistance and relapse. We hypothesized that understanding the evolution of the mutational landscape...
BCR-ABL1 and BCR-ABL1-like acute lymphoblastic leukemia (ALL) are two major pre-B cell acute leukemia subtypes characterized by genetic alterations affecting lymphoid-specific transcription factors. Studies examining the chain of genetic events necessary to develop leukemia established that the BCR-ABL1 fusion gene and kinase-activating BCR-ABL1-li...