
Torsten HaferlachMLL Münchner Leukämielabor GmbH | MLL · Cytomorphology
Torsten Haferlach
Prof. Dr. med. Dr. Phil
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Publications (2,155)
The definition of high‐risk (HR) multiple myeloma (MM) is still a matter of debate. We prospectively evaluated the HR detection using FISH in combination with SKY92 gene expression profiling in 258 MM patients (newly diagnosed [ND] MM: n = 109; relapsed/refractory [RR] MM: n = 149). HR SKY92 was significantly enriched in RRMM (57/121, 47.1%) compar...
Background:
Deletions (del) 5q in MDS typically occur either in MDS with low blasts and del(5q) (MDS-5q according to WHO) or in MDS with complex karyotype (CK). While MDS-5q are generally associated with a favorable prognosis and harbor TP53 alterations (alt) in 10-20% of these cases (most commonly single-hit), MDS with CK are associated with an un...
Background:
The most frequently mutated genes in clonal hematopoiesis (CH) occurring during aging are DNMT3A, TET2, and ASXL1 (DTA). DTA mutations (mut) also recurrently occur in overt myeloid malignancies.
Aim:
Analyze similarities and differences regarding incidence, co-aberrations and clonal hierarchy across CCUS, MDS and AML in patients with DT...
Background:
The 5th edition of the WHO Classification of Haematolymphoid Tumours (WHO 2022) highlights the importance of cytogenetic and molecular abnormalities in AML as disease-defining criteria. Mutations in genes frequently mutated in clonal hematopoiesis (CH) are also present in AML. However, it remains to be resolved in which order CH, other...
Background:
The approval of chimeric antigen receptor T-cells (CAR-T) represents an important milestone for the treatment of hematologic malignancies, including multiple myeloma (MM). Despite the unprecedented efficacy of CAR-T cell therapy, recent reports have however raised concern about the increased risk of treatment-related myeloid (t-MN, MN-p...
Introduction
The International Prognostic Scoring System (IPSS) and its revised version (IPSS-R) were developed using datasets from patients (pts) with untreated MDS. The cytogenetic risk groups used in IPSS-R were expanded to 5 groups from the 3 used in IPSS. Among the new groups introduced in IPSS-R is the “very complex” karyotype (VCK) where ≥4...
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...
Background:
SH2B3 acts as a negative regulator of cytokine signaling, cell proliferation and is involved in myelopoiesis. Mutations are known to occur both somatically as well as germline. Thus far, effects of these mutations have been mostly studied in the context of myeloproliferative neoplasms (MPN) and acute lymphoblastic leukemia (ALL). Howeve...
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: Response assessment is used to evaluate effectiveness of hypomethylating agent (HMA)-based therapy in myelodysplastic syndromes/neoplasms (MDS) in clinical practice and trials. Recently, the clinical response criteria (IWG 2023) and the clinical-molecular risk assessment (IPSS-M) in MDS were published. However, it remains unknown whet...
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...
Background & aim: Patients (pts) with MDS-del(5q), including those with TP53 multihit mutations, exhibit better outcomes compared to the general MDS population (Montoro et al., Blood 2024). However, approximately 20% of MDS-del(5q) eventually progress to acute myeloid leukemia (AML). Because the defining criteria of MDS-del(5q) exclude the presence...
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...
Background: Multiple myeloma (MM) is subdivided into groups based on recurrent cytogenetic abnormalities (CA). In addition, secondary CA and mutations (MUT) have been described that are associated with disease progression.
Aim: To comprehensively evaluate secondary alterations in MM subgroups.
Methods: Bone marrow samples (collected from 06/22 to 0...
Introduction:
Over recent years, the introduction and scalability of next-generation sequencing technologies have significantly expanded our knowledge of the genetic underpinnings of multiple myeloma (MM), a heterogeneous hematologic malignancy characterized by clonal plasma cell proliferation in the bone marrow. At present, cost-effective short-re...
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...
Acute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. We hypothesized that the numerous genomic rearrangements could reposition active enhancers near proto-oncogenes, leading to their aberrant expression. We developed pyjacker, a computational tool fo...
Extramedullary disease (EMD) is a high-risk feature of multiple myeloma (MM) and remains a poor prognostic factor even in the era of novel immunotherapies. Here we applied spatial transcriptomics (tomo-seq [n=2] and 10X Visium [n=12]), and single-cell RNA sequencing (scRNAseq [n=3]) to a set of 14 EMD biopsies to dissect the three-dimensional archi...
Mutations in the TP53 gene, particularly multihit alterations, have been associated with unfavorable clinical features and prognosis in patients diagnosed with myelodysplastic syndrome (MDS). Despite this, the role of TP53 gene aberrations in MDS with isolated deletion of chromosome 5 [MDS-del(5q)] remains unclear. This study aimed to assess the im...
Mutations in the cohesin complex components (STAG2, RAD21, SMC1A, SMC3, and PDS5B) are recurrent genetic drivers in myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML). Whether the different cohesin subunit mutations share clinical characteristics and prognostic significance is not known. We analyzed 790 cohesin-mutant patients from the...
Balanced rearrangements involving the KMT2A gene (KMT2Ar) are recurrent genetic abnormalities in acute myeloid leukemia (AML), but there is lack of consensus regarding the prognostic impact of different fusion partners. Moreover, prognostic implications of gene mutations co-occurring with KMT2Ar are not established. From the HARMONY AML database 20...
Single-gene missense mutations remain challenging to interpret. Here, we deploy scalable functional screening by sequencing (SEUSS), a Perturb-seq method, to generate mutations at protein interfaces of RUNX1 and quantify their effect on activities of downstream cellular programs. We evaluate single-cell RNA profiles of 115 mutations in myelogenous...
Background
TP53 mutations are associated with an adverse prognosis in acute myeloid leukemia (AML) and higher-risk myelodysplastic syndromes (HR-MDS). However, the integrated genetic, epigenetic, and immunologic landscape of TP53-mutated AML/HR-MDS is not well defined.
Objectives
To define the genetic, epigenetic, and immunologic landscape of TP53...
PURPOSE
Rare cancers constitute over 20% of human neoplasms, often affecting patients with unmet medical needs. The development of effective classification and prognostication systems is crucial to improve the decision-making process and drive innovative treatment strategies. We have created and implemented MOSAIC, an artificial intelligence (AI)–b...
Background
Rare oncogenic driver events, particularly affecting the expression or splicing of driver genes, are suspected to substantially contribute to the large heterogeneity of hematologic malignancies. However, their identification remains challenging.
Methods
To address this issue, we generated the largest dataset to date of matched whole gen...
Among the most common genetic alterations in the myelodysplastic syndromes (MDS) are mutations in the spliceosome gene SF3B1. Such mutations induce specific RNA missplicing events, directly promote ring sideroblast (RS) formation, and generally associate with more favorable prognosis. However, not all SF3B1 mutations are the same, and little is kno...
PURPOSE
Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only potentially curative treatment for patients with myelodysplastic syndromes (MDS). Several issues must be considered when evaluating the benefits and risks of HSCT for patients with MDS, with the timing of transplantation being a crucial question. Here, we aimed to develop...
PURPOSE
Decision about the optimal timing of a treatment procedure in patients with hematologic neoplasms is critical, especially for cellular therapies (most including allogeneic hematopoietic stem-cell transplantation [HSCT]). In the absence of evidence from randomized trials, real-world observational data become beneficial to study the effect of...
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T cell cancer. Mutations in IL7R have been analyzed genetically, but downstream effector functions such as STAT5A and STAT5B hyperactivation are poorly understood. Here, we studied the most frequent and clinically challenging STAT5BN642H driver in T cell development and immature...
Understanding the consequences of single amino acid substitutions in cancer driver genes remains an unmet need. Perturb-seq provides a tool to investigate the effects of individual mutations on cellular programs. Here we deploy SEUSS, a Perturb-seq like approach, to generate and assay mutations at physical interfaces of the RUNX1 Runt domain. We me...
Hemoglobinopathies including thalassemias are among the most frequent genetic disorders worldwide. Primarily, these entities result from germline variants in the globin gene clusters and their cis-acting regulatory elements, and thus the WHO classifies thalassemias as inherited diseases. Non-inherited disorders of globin chain synthesis mimicking t...
The landscape of haematological malignancies is constantly evolving, driven by advances in our understanding of their genetic basis. This has cumulated within the 5th Edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours published in short form in 2022 [1, 2] and being available in full length both as “Blue Book”...
In recent years, technology developments and increase in knowledge have led to profound changes in the diagnostics of haematologic neoplasms, particularly myeloid neoplasms. Therefore an updated, fifth edition of the World Health Organization (WHO) classification of haematolymphoid neoplasms (WHO-HAEM5) will be issued in 2024. In this context, we p...
PHF6 mutations (PHF6MT) are identified in various myeloid neoplasms (MN). However, little is known about the precise function and consequences of PHF6 in MN. Here we show three main findings in our comprehensive genomic and proteomic study. Firstly, we show a different pattern of genes correlating with PHF6MT in male and female cases. When analyzin...
Despite recent refinements in the diagnostic and prognostic assessment of CEBPA mutations in AML, several questions remain open, i.e. implications of different types of basic region leucin zipper (bZIP) mutations, the role of co-mutations and the allelic state. Using pooled primary data analysis on 1010 CEBPA-mutant adult AML patients, a comparison...
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...
Initial classification of acute leukemia involves the assignment of blasts to cell states within the hematopoietic hierarchy based on morphological and immunophenotypic features. Yet, these traditional classification approaches lack precision, especially at the level of immature blasts. Single-cell RNA-sequencing (scRNA-seq) enables precise determi...
It is still not fully understood how genetic haploinsufficiency in del(5q) MDS contributes to malignant transformation of hematopoietic stem cells. We asked how compound haploinsufficiency for Csnk1a1 and Egr1 in the common deleted region on chromosome 5 affects hematopoietic stem cells. Additionally, Trp53 was disrupted as the most frequently co-m...
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 treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechani...
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: The chromosomal alteration i(7)(p10) is a rare abnormality in hematological malignancies. It leads to a loss of the long arm (7q) and duplication of the short arm (7p) of chromosome 7. However, the presence, frequency and clinical implications of i(7)(p10) in hematological neoplasms has not been analyzed systematically to date.
Aim: (1)...
Background: The International Consensus Classification (ICC) introduced MDS/AML as a novel myeloid disease entity defined by 10-19% blasts in the absence of AML-defining recurrent genetic abnormalities. MDS/AML patients should be eligible for AML-like treatment approaches in clinical trials. It has recently been shown that the AML-based risk classi...
Background
In 2021 most of the Ukrainian patients with hematological diseases and in need of allogeneic hematopoietic cell transplantation (HCT) were treated outside the country with governmental funding or not treated. Only 147 autologous and 6 allogeneic HCT in adults (75 and 33 in children, respectively) in a country of 44 million population wer...
Background: Philadelphia-negative myeloproliferative neoplasms (Ph -MPN) are characterized by overproduction of differentiated hematopoietic cells mediated in the majority of cases by mutations in JAK2, MPL or CALR (MPN driver genes). Ph - MPN include polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) and MPN, uncla...
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...
Deregulation of MYC genes occurs in up to 70% of all human cancers and is associated with hallmarks of cancer including mitochondrial and ribosomal biogenesis, cell cycle progression, and metabolic abnormalities. TP53 regulates MYC while MYC suppresses TP53, suggesting counteracting negative feedback loops. Therefore, MYC or its function can be act...
Background: According to the 5 th edition of the WHO classification (WHO 2022) and the International Consensus Classification (ICC) the main parameters used for the definition of CCUS, MDS and AML are cytopenias, dysplasia, blast count and distinct genetic abnormalities. These entities represent a disease continuum as CCUS can progress to MDS and M...
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...
Introduction: The evaluation of novel drugs in hemato-oncology is hampered by relatively large sample sizes needed for sufficiently powered, randomized controlled trials (RCT). External control data are increasingly applied in prospective phase II and III studies, and might be derived from Real-World Data (RWD) sources, such as national cancer regi...
Background: AML and MDS cells accumulate mutations over years or even decades. In the current WHO 2022 classification, some mutations are listed as “defining genetic abnormalities” (WHO DGA). A long phase of clonal hematopoiesis may precede some, but not all, AML or MDS. There are multiple scenarios in which order clonal hematopoiesis, WHO DGAs, an...
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...
Initial disease classification within acute leukemia relies on identifying morphological and immunophenotypic features of hematopoietic differentiation retained by leukemic blasts. While existing approaches can classify leukemic cells into broad lineages, they lack precision in discerning between specific cell states, particularly at the level of i...
Myelodysplastic neoplasms (MDS) encompass clonal myeloid malignancies that are characterized by ineffective hematopoiesis, cytopenia, myelodysplasia, and recurrent genetic events. Apart from genetic abnormalities and the assessment of peripheral blood for cytopenia, cytomorphologic evaluation of bone marrow morphology is key in initial diagnosis an...
Improved classification of rare lymphoid neoplasms would be aided by a deeper understanding of their underlying molecular features and is important for diagnosis, prognosis and therapy. Tumor entities classified within the WHO category of splenic B cell lymphomas and leukemias often exhibit heterogenous, transecting features, and include hairy cell...
Introduction:Loss of function mutations in the cohesin complex ring components and modulators STAG2, RAD21, SMC1A, SMC3, and PDS5B are recurrent genetic drivers in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and MDS/myeloproliferative neoplasm (MPN) overlap syndromes. However, whether different cohesin subunit mutations share dis...
Introduction:
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by accumulation of abnormal hematopoietic stem and progenitor cells. TP53 mutations, present in 8 - 30 % of AML, are associated with high risk of relapse and poor prognosis. The mechanisms underlying their persistence are not well understood. Here, we attempt to des...
Background:
Acute myeloid leukemia (AML) is a heterogeneous disease with high disease-related mortality and allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option for a large proportion of patients. However, allo-HSCT has a significant transplant-related mortality (TRM), so a careful evaluation between risk...
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)...
Introduction: AI is becoming an integral part of diagnostic workup solutions worldwide. Using our vast database of flow cytometry data of hematologic neoplasms, we develop AI-powered workflows to support high-throughput routine diagnostics. As one of our most frequent requests is proof / exclusion of B-cell lymphoma, we initially focus on mature B-...
Background: Analysis of bone marrow is the gold standard in patients with unexplainable cytopenia for diagnosing (or excluding) myelodysplastic neoplasm (MDS). Besides morphology also molecular genetics and cytogenetics are currently assessed from BM as both are required for diagnosis and risk stratification. Substitution of BM analysis with periph...
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...