ORCID Profile
0000-0003-4870-3445
Current Organisation
Goethe-Universität Frankfurt am Main
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Publisher: Springer Science and Business Media LLC
Date: 13-07-2017
DOI: 10.1038/LEU.2017.213
Publisher: Research Square Platform LLC
Date: 21-03-2023
DOI: 10.21203/RS.3.RS-2697729/V1
Abstract: IKZF1 deletions are associated with an increased risk of relapse in B-cell precursor acute lymphoblastic leukemia (B-ALL), and their accurate detection has great clinical impact. Here, we included four international cohorts of pediatric and adult patients with B-ALL, and reviewed literature to illustrate the recombination map of IKZF1 deletions, with a focus at non-recurrent deletions. We provide a substantial basis for the improvement of diagnostic methods based on MLPA and multiplex PCR for the identification of IKZF1 deletions, and also demonstrate that rare IKZF1 deletions increase the incidence of relapse in these patients. Of note, non-recurrent deletions comprised a wide range of alterations, but the majority were Δ1 and Δ1–3. They were often associated with reciprocal IKZF1 fusions. So far, a total of 23 IKZF1 gene fusions were identified in B-ALL. We also verified the occurrence of the heptamer sequence (E-value: 9.9 x 10 − 9 ) and an enrichment of GC nucleotides (71% versus 56% P value = 4.9 x 10 − 3 ) exclusively within breakpoint clusters, suggesting that RAG recombination and TdT activity may promote the majority of IKZF1 deletions, although rare types of alterations may be associated with other molecular mechanism of leukemogenesis, such as microhomology-mediated end joining.
Publisher: Springer Science and Business Media LLC
Date: 29-06-2023
Publisher: Wiley
Date: 26-02-2021
DOI: 10.1002/PBC.28922
Abstract: We report on the Australian experience of blinatumomab for treatment of 24 children with relapsed/refractory precursor B‐cell acute lymphoblastic leukaemia (B‐ALL) and high‐risk genetics, resulting in a minimal residual disease (MRD) response rate of 58%, 2‐year progression‐free survival (PFS) of 39% and 2‐year overall survival of 63%. In total, 83% ( n = 20/24) proceeded to haematopoietic stem cell transplant, directly after blinatumomab ( n = 12) or following additional salvage therapy ( n = 8). Four patients successfully received CD19‐directed chimeric antigen receptor T‐cell therapy despite prior blinatumomab exposure. Inferior 2‐year PFS was associated with MRD positivity (20%, n = 15) and in KMT2A ‐rearranged infants (15%, n = 9). Our findings highlight that not all children with relapsed/refractory B‐ALL respond to blinatumomab and factors such as blast genotype may affect prognosis.
Publisher: American Association for Cancer Research (AACR)
Date: 12-03-2015
DOI: 10.1158/1078-0432.CCR-14-2300
Abstract: Purpose: Although the overall cure rate for pediatric acute lymphoblastic leukemia (ALL) approaches 90%, infants with ALL harboring translocations in the mixed-lineage leukemia (MLL) oncogene (infant MLL-ALL) experience shorter remission duration and lower survival rates (∼50%). Mutations in the p53 tumor-suppressor gene are uncommon in infant MLL-ALL, and drugs that release p53 from inhibitory mechanisms may be beneficial. The purpose of this study was to assess the efficacy of the orally available nutlin, RG7112, against patient-derived MLL-ALL xenografts. Experimental Design: Eight MLL-ALL patient-derived xenografts were established in immune-deficient mice, and their molecular features compared with B-lineage ALL and T-ALL xenografts. The sensitivity of MLL-ALL xenografts to RG7112 was assessed in vitro and in vivo, and the ability of RG7112 to induce p53, cell-cycle arrest, and apoptosis in vivo was evaluated. Results: Gene-expression analysis revealed that MLL-ALL, B-lineage ALL, and T-ALL xenografts clustered according to subtype. Moreover, genes previously reported to be overexpressed in MLL-ALL, including MEIS1, CCNA1, and members of the HOXA family, were significantly upregulated in MLL-ALL xenografts, confirming their ability to recapitulate the clinical disease. Exposure of MLL-ALL xenografts to RG7112 in vivo caused p53 upregulation, cell-cycle arrest, and apoptosis. RG7112 as a single agent induced significant regressions in infant MLL-ALL xenografts. Therapeutic enhancement was observed when RG7112 was assessed using combination treatment with an induction-type regimen (vincristine/dexamethasone/L-asparaginase) against an MLL-ALL xenograft. Conclusions: The utility of targeting the p53–MDM2 axis in combination with established drugs for the management of infant MLL-ALL warrants further investigation. Clin Cancer Res 21(6) 1395–405. ©2015 AACR.
Publisher: American Society of Hematology
Date: 15-11-2013
DOI: 10.1182/BLOOD.V122.21.2552.2552
Abstract: The regulation of hematopoietic lineage fate and commitment is fundamental to normal and malignant hematopoiesis. Switches between lymphoid and myeloid lineages in leukemia are rare and associated with poor clinical outcome, but potentially very informative regarding the regulation of hematopoietic lineage commitment. In contrast to therapy-related acute leukemia (AL) after a first primary leukemia, lineage-switch ALs arise from a common pre-leukemic or leukemic clone and share a founder mutation, most often rearrangement of MLL at 11q23. The majority of switches are from acute lymphoblastic leukemia (ALL) to acute myeloid leukemia (AML) however, conversions from myeloid to lymphoid and even oscillations between the two lineages have been observed, although the molecular mechanisms underlying lineage switch have not yet been identified. Here we describe a male patient who presented at 9 months of age with a t(4 )-positive B-ALL and was subsequently treated according to the Interfant06 protocol. He achieved complete remission, but relapsed at the age of 4 years with a t(4 )-positive AML. He underwent allogeneic BM transplantation and has remained in remission 13 months. Sanger sequencing revealed identical translocation breakpoints in the ALL and AML s les, demonstrating a lymphoid to myeloid lineage switch with a common pre-leukemic or leukaemic cell of origin for both ALs. Interestingly, whereas the AML shows no V(D)J rearrangements, we found incomplete rearrangements in the ALL cells indicating a ProB cell origin. In line with this observation, B-ALL cells expressed 6-fold and 120-fold higher levels of PAX5 and EBF1, respectively, compared to AML blast cells. Microsatellite instability measurements argued against a strong therapy-associated impairment of DNA mismatch repair in the AML. The translocation t(4 ) is the most frequently found chromosomal rearrangement in infant leukaemia and is almost exclusively associated with ALL at presentation, suggesting a strong instructive potential towards the lymphoid cell fate. However, the occurrence of lineage switch in t(4 ) AL demonstrates that this instruction can be overcome by as yet unknown mechanisms. Exome sequencing identified 16 and 98 novel somatic variants in the diagnostic ALL s le (0.23 mutations per Mb) and AML (1.4 mutations per Mb), respectively, of which 10 were shared. Of the total novel somatic mutations, there were 1 and 12 non-synonymous alterations in the B-ALL and AML, respectively, of which one was shared. RNA sequencing confirmed that all 12 genes with non-synonymous mutations were expressed in AML blast cells, and all belonged to the top 25% of expressed genes in both the AML and B-ALL. Genes carrying non-synonymous somatic AML-specific mutations include CHD4 (12p13, NuRD helicase, chromatin maintenance, DNA repair, lineage fidelity, part of MLL complex), NCOA2 (8q13, also known at TIF2 and part of the MOZ/TIF2 fusion gene, cofactor of nuclear receptors including VDR and NR3C1 control of myeloid differentiation, putative tumour suppressor), CEP164 (11q23, centrosome protein involved in microtubule organization, DNA damage response and chromosome segregation) and PPP1R7 (2q37, regulatory subunit of protein phosphatase 1, control of mitosis, regulator of AURKB). All amino acid residues predicted to be mutated are conserved between several species. Each of the identified mutations is located in functionally relevant regions and may, thus, interfere with protein function. Notably, exome and RNAseq showed that all 12 of the AML-specific non-synonymous mutations were found in at least 40% of the reads covering the corresponding genomic positions (the s le analysed constituted 80% blast material), thus suggesting heterozygosity for each mutation and that all mutations are common to the major leukemic clone. Taken together, these data suggest that the B-ALL and AML share a common ancestral pre-leukemic or leukemic cell of origin. Whilst the B-ALL revealed few novel somatic mutations, the change in lineage is associated with the acquisition of a substantial number of novel mutations indicating significant clonal evolution preceding the emergence of myeloid neoplasia. These data identify candidate mutations/genes which may overcome lineage instruction by a leukemic master regulator such as MLL/AF4 and which may therefore play an essential role in the control of hematopoietic lineage fate. No relevant conflicts of interest to declare.
Publisher: American Society of Hematology
Date: 27-10-2022
Abstract: The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukemia, resulting in poor clinical outcomes caused by resistance to chemotherapies and immunotherapies. In this study, the myeloid relapses shared oncogene fusion breakpoints with their matched lymphoid presentations and originated from various differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programs, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing, or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4+ cell models, indicating that lineage switching in MLL/AF4 leukemia is driven and maintained by disrupted epigenetic regulation.
Publisher: Springer Science and Business Media LLC
Date: 27-09-2021
DOI: 10.1038/S41467-021-25963-Z
Abstract: High-throughput sequencing describes multiple alterations in in idual tumors, but their functional relevance is often unclear. Clinic-close, in idualized molecular model systems are required for functional validation and to identify therapeutic targets of high significance for each patient. Here, we establish a Cre-ER T2 -loxP (causes recombination, estrogen receptor mutant T2, locus of X-over P1) based inducible RNAi- (ribonucleic acid interference) mediated gene silencing system in patient-derived xenograft (PDX) models of acute leukemias in vivo. Mimicking anti-cancer therapy in patients, gene inhibition is initiated in mice harboring orthotopic tumors. In fluorochrome guided, competitive in vivo trials, silencing of the apoptosis regulator MCL1 (myeloid cell leukemia sequence 1) correlates to pharmacological MCL1 inhibition in patients´ tumors, demonstrating the ability of the method to detect therapeutic vulnerabilities. The technique identifies a major tumor-maintaining potency of the MLL-AF4 (mixed lineage leukemia, ALL1-fused gene from chromosome 4) fusion, restricted to s les carrying the translocation. DUX4 (double homeobox 4) plays an essential role in patients’ leukemias carrying the recently described DUX4-IGH (immunoglobulin heavy chain) translocation, while the downstream mediator DDIT4L (DNA-damage-inducible transcript 4 like) is identified as therapeutic vulnerability. By in idualizing functional genomics in established tumors in vivo, our technique decisively complements the value chain of precision oncology. Being broadly applicable to tumors of all kinds, it will considerably reinforce personalizing anti-cancer treatment in the future.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-02-2021
DOI: 10.1200/JCO.20.02333
Abstract: Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of KMT2A gene rearrangements and poor outcome. We evaluated the value of minimal residual disease (MRD) in infants with KMT2A-rearranged ALL treated within the Interfant-06 protocol, which compared lymphoid-style consolidation (protocol IB) versus myeloid-style consolidation (araC, daunorubicin, etoposide/mitoxantrone, araC, etoposide). MRD was measured in 249 infants by DNA-based polymerase chain reaction of rearranged KMT2A, immunoglobulin, and/or T-cell receptor genes, at the end of induction (EOI) and end of consolidation (EOC). MRD results were classified as negative, intermediate ( 5 × 10 −4 ), and high (≥ 5 × 10 −4 ). EOI MRD levels predicted outcome with 6-year disease-free survival (DFS) of 60.2% (95% CI, 43.2 to 73.6), 45.0% (95% CI, 28.3 to 53.1), and 33.8% (95% CI, 23.8 to 44.1) for infants with negative, intermediate, and high EOI MRD levels, respectively ( P = .0039). EOC MRD levels were also predictive of outcome, with 6-year DFS of 68.2% (95% CI, 55.2 to 78.1), 40.1% (95% CI, 28.1 to 51.9), and 11.9% (95% CI, 2.6 to 29.1) for infants with negative, intermediate, and high EOC MRD levels, respectively ( P .0001). Analysis of EOI MRD according to the type of consolidation treatment showed that infants treated with lymphoid-style consolidation had 6-year DFS of 78.2% (95% CI, 51.4 to 91.3), 47.2% (95% CI, 33.0 to 60.1), and 23.2% (95% CI, 12.1 to 36.4) for negative, intermediate, and high MRD levels, respectively ( P .0001), while for myeloid-style–treated patients the corresponding figures were 45.0% (95% CI, 23.9 to 64.1), 41.3% (95% CI, 23.2 to 58.5), and 45.9% (95% CI, 29.4 to 60.9). This study provides support for the idea that induction therapy selects patients for subsequent therapy infants with high EOI MRD may benefit from AML-like consolidation (DFS 45.9% v 23.2%), whereas patients with low EOI MRD may benefit from ALL-like consolidation (DFS 78.2% v 45.0%). Patients with positive EOC MRD had dismal outcomes. These findings will be used for treatment interventions in the next Interfant protocol.
Publisher: Springer Science and Business Media LLC
Date: 21-03-2019
Publisher: Springer Science and Business Media LLC
Date: 05-04-2023
DOI: 10.1038/S41375-023-01877-1
Abstract: Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A -partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5’- KMT2A , two patients had a 5’- KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A , 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.
No related grants have been discovered for Rolf Marschalek.