Wencke Walter

MLL Münchner Leukämielabor GmbH | MLL

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the presence of somatic mutations in hematopoietic stem and progenitor cells (HSPC) and is considered a precursor to myeloid neoplasia. HSPC in DNMT3A and TET2 mutant CHIP show a proliferative advantage over time, but the underlying mechanisms have not been completely unrave...

B cell precursor acute lymphoblastic leukemia (BCP-ALL) molecular subtypes are defined by genomic drivers and corresponding gene expression signatures. Inference of underlying genomic aberrations from transcriptome sequencing (RNA-Seq) enables BCP-ALL subtype allocation based on consistency of driver call and corresponding gene expression signature...

Introduction: AML with NPM1 mutation represents the largest genetic AML entity, detected in around 30% of adults with newly diagnosed disease. Despite overall favorable outcome it is highly heterogeneous with respect to mutational pattern, clonal hierarchy, blast immunophenotypes (IP) and gene expression profiles. Patients therefore may benefit fro...

Introduction: The dic(9;20)(p11-13;q11) chromosomal aberration is a rare occurrence in acute lymphoblastic leukemia (ALL), more commonly identified in pediatric BCP-ALL (2-3%) than in adults (<2%). With the integration of BCP-ALL subtype classification by gene expression analysis into standard diagnostic protocols, as endorsed by WHO 2022 and ICC 2...

The recent FDA approval of Imetelstat, a new class of antineoplastic drugs for the treatment of MDS1 opens the question on whether telomere content (TC) and/or telomerase function might constitute therapeutic targets and diagnostic biomarkers. Early studies have not specifically delved in elucidating such possibility. In general, cancer relies on e...

CCAAT-enhancer-binding proteins (C/EBP) are important regulators of myeloid differentiation and cell cycle control. The C/EBP family member CEBPE has been implicated in B precursor acute lymphoblastic leukemia (BCP-ALL) through IGH locus gene fusions and rare germline single nucleotide variants. ‘ZEB2 (p.H1038R)/IGH::CEBPE‘ BCP-ALL is a provisional...

B‐acute lymphoblastic leukaemia (B‐ALL) is a haematological disease resulting from haematopoietic system dysfunction, leading to the unchecked growth of immature B lymphoblasts. The disease's complexity is underscored by the spectrum of genetic aberrations that underlie B‐ALL entities, necessitating advanced genetic analyses for precise classificat...

Despite major therapeutic advances in the treatment of acute lymphoblastic leukemia (ALL), resistances and long-term toxicities still pose significant challenges. Cyclins and their associated cyclin-dependent kinases are one focus of cancer research when looking for targeted therapies. We discovered cyclin C as a key factor for B-ALL development an...

UBA1, an X-linked gene, encodes one of the only two ubiquitin E1 enzymes, playing a pivotal role in initiating one of the most essential post-translational modifications. In late 2020, partial loss-of-function mutations in UBA1 within hematopoietic stem and progenitor cells were found to be responsible for VEXAS Syndrome, a previously unidentified...

Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal disorders characterized by aberrant hematopoietic proliferation and an intrinsic risk of progression to blast phase. The WHO classification 2022 identifies chronic myeloid leukemia and the BCR::ABL1 negative MPNs polycythemia vera, primary myelofibrosis and essential thrombocyth...

Patients with T- and NK-cell neoplasms frequently have somatic STAT5B gain-of-function mutations. The most frequent STAT5B mutation is STAT5BN642H, which is known to drive murine T-cell leukemia although its role in NK-cell malignancies is unclear. Introduction of the STAT5BN642H mutation into human NK-cell lines enhances their potential to induce...

Distinct diagnostic entities within BCR::ABL1-positive ALL are currently defined (ICC): 'lymphoid-only', with BCR::ABL1 observed exclusively in lymphatic precursors versus 'multilineage', where BCR::ABL1 is also present in other hematopoietic lineages. Here, we analyzed transcriptomes of n=327 BCR::ABL1-positive ALL patients (age: 2 years - 84 year...

Systemic mastocytosis (SM) is defined by expansion and accumulation of neoplastic mast cells (MC) in the bone marrow (BM) and extracutaneous organs. Most patients harbor a somatic KIT D816V mutation, which leads to growth factor independent KIT activation and accumulation of MC. Tumor necrosis factor-alpha (TNF) is a pro-apoptotic and inflammatory...

The World Health Organization Classification of Hematolymphoid Tumors (WHO) and the International Consensus Classification (ICC) of 2022 introduced major changes to the definition of CMML. To assess qualitative and quantitative implications for patient care, we started with 3,311 established CMML cases (according to WHO 2017 criteria) and included...

Background: Gene fusions are a frequent event in acute myeloid leukaemia (AML). It is estimated that about 40% of AML patients harbour a cytogenetic abnormality resulting in a gene fusion. However, AML with t(4;12)(q12;p13) is very rare, but it is often accompanied by an aggressive clinical course and a poor prognosis. As frequently indicated by fl...

Micromegakaryocytes (micro-MKs), an unequivocal myeloid dysplastic feature in adults, are present in 15-20% of myelodysplastic neoplasms (MDS). We recently associated the detection of these small megakaryocytes with a mono- or bi-lobated nucleus in bone marrow (BM) smears of MDS patients with an unfavorable prognosis. The aim of the present study w...

Background: The 5 th edition of the WHO classification newly included myeloid precursor lesions introducing CCUS as an entity. CCUS is defined as clonal hematopoiesis (CH) in the presence of unexplained, persistent cytopenia requiring detection of either somatic mutation in certain CH associated genes or clonal chromosomal abnormalities. Aim: Chara...

Background: As reported in our preliminary work (Blood (2022) 140 (Supplement 1): 9142-9143) myeloid neoplasms (MN) with MYC-positive double minutes (dmin) are mostly AML and often show a cytomorphological proximity to APL. We here now present detailed genotypical and phenotypical characteristics to address the question if MN with MYC dmin might re...

Clonal hematopoiesis of indeterminate potential (CHIP) describes the age-related acquisition of somatic mutations in hematopoietic stem/progenitor cells (HSPC) leading to clonal blood cell expansion and variable risk of progression to myeloid malignancy. DNMT3A is the most commonly mutated gene and while single mutations do not raise the likelihood...

Background: The advantages of genome-wide sequencing approaches over conventional methods in CLL diagnostics are a matter of debate and exact guidelines for the application of next-generation sequencing in a diagnostic context are currently missing. Aim: Compare the accuracy of whole genome sequencing (WGS) and whole transcriptome sequencing (WTS)...

Background: Since the introduction of tyrosine kinase inhibitor therapy survival has substantially improved in CML. However, a subset of patients become resistant and progress to blast phase. Still the underlying genomic changes are not completely understood. Cohort & Methods: We studied 21 CML patients with paired sample material available from di...

Two developmental trajectories are acknowledged in BCR::ABL1-positive acute lymphoblastic leukemia (ALL) as distinct diagnostic entities by the ICC classification: ‘lymphoid-only’ with BCR::ABL1 restricted to the leukemic B precursor compartment vs. ‘multilineage’ with BCR::ABL1 involvement also in other hematopoietic lineages. Diagnostic standards...

Background: UBA1 variants have recently been described as causative to the somatic hematoinflammatory disease VEXAS Syndrome. Previously, the features of M41 and non-M41 variants regarding their diagnoses and inflammatory transcriptome in comparison to other patients (pts) diagnosed with hematological malignancies (HM) have been described ( Leukemi...

Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal disorders characterized by aberrant hematopoietic proliferation and an intrinsic risk of progression to blast phase. The WHO classification 2022 identifies chronic myeloid leukemia and the BCR :: ABL1 negative MPNs polycythemia vera, primary myelofibrosis and essential thrombocy...

B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging data report that downregulation of G-protein-coupled receptor family C group 5 member D (GPRC5D) protein often occur...

Current classifications (World Health Organization-HAEM5/ICC) define up to 26 molecular B-cell precursor acute lymphoblastic leukemia (BCP-ALL) disease subtypes by genomic driver aberrations and corresponding gene expression signatures. Identification of driver aberrations by transcriptome sequencing (RNA-Seq) is well established, while systematic...

Several clinical and genetic factors impact on overall survival (OS) in myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML), including complex karyotype (CK), TP53 allelic state and blast count. We analysed the interplay of these factors by performing Cox regression analysis and by determining the frequency of TP53 single hit (sh) and...

BACKGROUND AND AIMS In 2020, three somatic mutations in the X-linked gene UBA1, coding for an essential ubiquitin activating enzyme, were reported to cause VEXAS syndrome, a novel haemato-inflammatory disease that manifests with both cytopenias and autoinflammation.1 The mutations alter the start codon (M41) of the cytoplasmic isoform of UBA1, resu...

B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging data report that downregulation of G protein coupled receptor family C group 5 member D (GPRC5D) protein often occur...

UBA1 is an X-linked gene and encodes an ubiquitin-activating enzyme. Three somatic mutations altering the alternative start codon (M41) in UBA1 in hematopoietic precursor cells have recently been described, resulting in a syndrome of severe inflammation, cytopenias, and the presence of intracellular vacuoles in hematopoietic precursors - termed VEX...

Current classifications (WHO-HAEM5 / ICC) define up to 26 molecular B-cell precursor acute lymphoblastic leukemia (BCP-ALL) disease subtypes, which are defined by genomic driver aberrations and corresponding gene expression signatures. Identification of driver aberrations by RNA-Seq is well established, while systematic approaches for gene expressi...

The future of clinical diagnosis and treatment of hematologic diseases will inevitably involve the integration of artificial intelligence (AI)-based systems into routine practice to support the hematologists' decision making. Several studies have shown that AI-based models can already be used to automatically differentiate cells, reliably detect ma...

Myeloperoxidase (MPO) gene alterations with variable clinical penetrance have been found in hereditary MPO deficiency, but their leukemia association in patients and carriers has not been established. Germline MPO alterations were found to be significantly enriched in myeloid neoplasms: 28 pathogenic/likely pathogenic variants were identified in 10...

The DNA damage response (DDR) pathway is frequently deregulated in cancer and it represent an attractive therapeutic opportunity. In acute myeloid leukemia (AML), different mechanisms of DDR deregulation have been identified, but a systematic investigation on DDR alterations is missing. To understand how the DDR pathways contribute to leukemogenesi...

Background Haploinsufficiency (HI) resulting from deletion of the long arm of chromosome 5 [del(5q)] and the accompanied loss of heterozygosity are likely key pathogenic factors in del(5q) myeloid neoplasia (MN) although the consequences of del(5q) have not been yet clarified. Methods Here, we explored mutations, gene expression and clinical pheno...

Aberrant somatic hypermutation (aSHM) can target proto-oncogenes and drive oncogenesis. In mantle cell lymphoma (MCL), CCND1 is targeted by aSHM in the non-nodal subtype (nnMCL), giving rise to exon1 encoded mutant proteins like E36K, Y44D, and C47S that contribute to lymphomagenesis by virtue of their increased protein stability and nuclear locali...

Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK) is characterized by clonal expansion of natural killer (NK) cells where the underlying genetic mechanisms are incompletely understood. In the present study, we report somatic mutations in the chemokine gene CCL22 as the hallmark of a distinct subset of CLPD-NK. CCL22 mutations w...

Transcriptome sequencing has identified multiple subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL) of prognostic significance, but a minority of cases lack a known genetic driver. Here, we used integrated whole genome (WGS) and transcriptome sequencing (RNA-seq), enhancer mapping and chromatin topology analysis to identify previously un...

Background: Myelodysplastic syndromes (MDS) comprise a heterogeneous group of diseases classified by comprehensive diagnostics. Identification of homogeneous subgroups is desirable to understand differences in clinical course and to develop targeted treatment approaches. We identified a specific CD11b/CD16 expression pattern in granulocytes associ...

Introduction/Methods: Enzymes that modify histone H3 at lysine 27 (H3K27) to thereby regulate gene transcription (epigenetic enzymes) are recurrently inactivated by deletion and/or mutation in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and acute myeloid leukemias (AML). Frustrating understanding of mechanisms is that writer...

Background: Systemic mastocytosis (SM) is a hematologic neoplasm characterized by the infiltration of clonal mast cells in the bone marrow or other extra-cutaneous organs. The clinical course varies between advanced and non-advanced (indolent and smoldering SM) forms of SM. The vast majority of patients harbor the activating D816V mutation in the K...

Background: TP53 mutations in acute myeloid leukemia (AML) are associated with complex karyotype, high incidence of minimal residual disease (MRD), and high risk of relapse (Döhner et al., 2017; Giacomelli et al., 2018). While numerous novel treatment regimens, including the combination of the BCL2 inhibitor venetoclax (VEN) and hypomethylating age...

Background: FISH is the gold standard for genetic characterization and risk stratification of multiple myeloma (MM) at diagnosis. Retrospective studies have shown the potential of whole genome sequencing (WGS) to gain new insights into MM genetics. With respect to clinical application, we prospectively performed FISH and WGS in parallel in patients...

The prevailing theory in del(5q) is that haploinsuffciency (HI) stemming from deletion and not simply LOH (loss of heterozygosity) is the culprit in clonal evolution. To date no haploinsufficient gene has been found to be the leukemogenic factor conveying growth advantage, but various other genes have been found to be important for phenotypic featu...

Background: TP53 is altered in ~50% of human cancers. Alterations mainly include mutations and/or deletions, but also copy-neutral loss of heterozygosity (CN-LOH) was reported. Frequently, both TP53 alleles are altered (by mutation + deletion, mutation + CN-LOH or ≥2 mutations), leading to a "double hit" event. Aim: Analysis of TP53 aberrations usi...

Background: Copy-neutral loss-of-heterozygosity (CN-LOH) - not detectable by chromosome banding analysis - is gaining importance as a prognostic factor and can either cause the duplication of an activating mutation in an oncogene, the deletion of a tumor suppressor gene or the gain/loss of specific methylated regions. However, examination for possi...

Background: Currently, hematologic neoplasms are diagnosed using a combination of methods, which require complex equipment and highly skilled clinical laboratory scientists and technicians - scarce resources. WGS and WTS could streamline this process and become a singular method. Interpretation of WGS and WTS data in a diagnostic setting is extreme...

Background: The current routine genetic work-up in hematological malignancies includes chromosome banding analysis (CBA) to detect complete or partial chromosomal deletions and fusions, and the identification of point mutations and small deletions or insertions by sequencing panels (max. length ~50 bp). Deletions of individual genes (e.g. IKZF1 in...

Background: In AML and ALL the application of WHO classification and ELN guidelines requires a combination of cytogenetics and targeted sequencing for specific mutations to determine the diagnostic and prognostic subgroup. WGS and WTS have emerged as comprehensive techniques that allow the simultaneous analysis and identification of all genetic alt...

In recent decades, there has been a substantial increase in recognition of germline (GL) predisposition to MN. Some congenital blood disorders predispose to subsequent myeloid neoplasia (MN). Severe congenital neutropenia (SCN) and Fanconi anemia serving as prominent examples. There is emerging evidence that heterozygous variants of disease recessi...

The differential diagnosis of myeloid malignancies is challenging and subject to inter-observer variability. We used clinical and next-generation sequencing (NGS) data to develop a machine learning model for the diagnosis of myeloid malignancies independent of bone marrow biopsy data based on a three institution, international cohort of patients. T...

Acquired somatic mutations are crucial for the development of the majority of cancers. We performed a comprehensive comparative analysis of the mutational landscapes and their correlation to CHIP-related (clonal hematopoiesis of indeterminate potential) mutations and patient age of 122 genes in 3096 cases with 28 different hematological malignancie...