Claus Meyer

Diagnostic Center of Acute Leucemia (DCAL) · Institute of Pharmaceutical Biology, Goethe University Frankfurt, Germany

Measurable residual disease (MRD) monitoring in childhood acute myeloid leukemia (AML) is used to assess response to treatment and for early detection of imminent relapse. In childhood AML, MRD is typically evaluated using flow cytometry, or by quantitative detection of leukemia-specific aberrations at the mRNA level. Both methods, however, have si...

The cellular ontogeny and location of the MLL-breakpoint influence the capacity of MLL-edited CD34+ HSPCs to initiate pro-B-ALL, and recapitulate the molecular features of MLL-AF4+ infant B-ALL patients. We provide key insights into the cellular-molecular leukemogenic determinants of MLL-AF4+ infant B-ALL.

KMT2A-rearranged (KMT2A-r) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is widely recognized as a high-risk leukemia in both children and adults. However, there is a paucity of data on adults treated in recent protocols and the optimal treatment strategy for these patients is still a matter of debate. In this study, we set out to refine...

Pediatric acute myeloid leukemia (pedAML) is a highly heterogeneous disease making standardized measurable residual disease (MRD) assessment challenging. Currently, patient-specific DNA-based assays are only rarely applied for MRD assessment in pedAML. We tested whether quantification of genomic breakpoint specific sequences via quantitative PCR (g...

KMT2A-rearranged acute lymphoblastic infant leukemia (KMT2A-r iALL) is associated with outsize risk of relapse and relapse mortality. We previously reported strong upregulation of the immediate early gene EGR3 in KMT2A::AFF1 iALL at relapse; now we provide analyses of the EGR3 regulome, which we assessed through binding and expression target analys...

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 partn...

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, wi...

The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukaemia resulting in poor clinical outcomes due to resistance towards chemo- and immuno-therapies. Here we show that the myeloid relapses share oncogene fusion breakp...

The most frequent genetic aberration leading to infant ALL (iALL) is the chromosomal translocation t(4;11), generating the fusion oncogenes KMT2A:AFF1 and AFF1:KMT2A, respectively. KMT2A-r iALL displays a dismal prognosis through high relapse rates and relapse-associated mortality. Relapse occurs frequently despite ongoing chemotherapy and without...

The KMT2A (MLL) gene rearrangements (KMT2A-r) are associated with a diverse spectrum of acute leukemias. Although most KMT2A-r are restricted to nine partner genes, we have recently revealed that KMT2A-USP2 fusions are often missed during FISH screening of these genetic alterations. Therefore, complementary methods are important for appropriate det...

About 25% of the patients with the translocation t(11;19)(q23;p13.3)/KMT2A-MLLT1 present three-way or more complex fusions, associated with a worse prognosis, suggesting that a particular mechanism creates functional KMT2A fusions for this condition. In this work, we show a cryptic three-way translocation t(9;11;19). Interestingly, long-distance in...

Chromosomal rearrangements of the KMT2A gene are associated with acute leukemias and myelodysplastic syndromes. The large number of known KMT2A fusions (>100) renders a precise diagnosis a demanding task. More than 50% of all KMT2A partner genes have been analyzed at the DCAL, including the novel partner genes BCAS4, FAM13A, RANBP3, and STK4. Even...

Infant t(4;11) acute lymphoblastic leukemia (ALL) is associated with a high relapse rate with 4-year event-free survival (EFS) of only 36%. Relapse has been shown to be the major cause of death as 83% of relapsed infant t(4;11) ALL patients die within three years of diagnosis. Therefore, it is of utmost therapeutic interest to elucidate molecular m...

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a subgroup of T-cell acute lymphoblastic leukemia (T-ALL) that shares similarities with both T-ALL and acute myeloid leukemia (AML). We present a unique case of pediatric ETP-ALL with a t(6;11)(q27;q23)/ KMT2A-AFDN translocation in which leukemia cells underwent lineage conversion to...

Introduction KMT2A (MLL) gene rearrangements (KMT2A -r) are associated with diverse acute leukemias. Given the high number of KMT2A fusions, screening methods guide their detection regardless of partner gene. For instance, immunophenotyping using an anti-CSPG4 (NG2) antibody or split-signal fluorescence in situ hybridization (FISH) are routinely us...

Objectives KMT2A gene aberrations are more frequent in infants less than one year (yr) of age, accounting for about 70% of acute lymphoblastic leukemia (ALL) patients, and about 30% are diagnosed with acute myeloid leukemia (AML). The most common abnormality found in these patients is the translocation t(11;19)(q23;p13.3), corresponding to 22% of K...

Background The detection of KMT2A gene rearrangements have an important impact on the prognosis and management of acute leukemias. These alterations most commonly involve reciprocal translocations at specific breakpoint regions within KMT2A. To date, more than 100 translocation partner genes of KMT2A have been identified, with different effects on...

The fusion gene MLL-AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. However, relapse can be associated with a switch from acute lymphoblastic to acute myeloid leukaemia. Here we show that these myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate in either early, mult...

Therapy-related acute myeloid leukemia (t-AML) following treatment with topoisomerase-II inhibitors has been increasingly reported. These compounds (e.g. etoposide) promote DNA damage and are associated with KMT2A rearrangements. They are widely used as first-line treatment in hemophagocytic lymphohistiocytosis (HLH). Here we describe a newborn who...

Background: The detection of KMT2A gene rearrangements have an important impact on the prognosis and management of acute leukemias. These alterations most commonly involve reciprocal translocations at specific breakpoint regions within KMT2A. To date, more than 100 translocation partner genes of KMT2A have been identified, with different effects on...

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...

PURPOSE 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 c...

The translocation MLL-AF4 defines a high-risk subtype of acute leukaemia which, uniquely amongst MLL translocations, is almost exclusively associated with a pro-B lymphoid phenotype. However, the ability to switch lineage at relapse allowed interrogation of the cellular origin and lineage determinants of this leukaemia. The origin of MLL-AF4 lympho...

Patients with childhood acute myeloid leukemia (AML) with complex karyotypes (CKs) have a dismal outcome. However, for patients with a KMT2A rearrangement (KMT2A-r), the prognosis appears to depend on the fusion partner gene rather than the karyotype structure. Thus, a precise characterization of KMT2A-r and the fusion partner genes, especially in...

IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in both childhood and adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Previously, we revealed that COBL is a hotspot for breakpoints in leukemia and could promote IKZF1 deletions. Through an international collaboration, we provide a detailed genetic and clinical picture of B-...

Identification of Cryptic Recombination Signal Sequences Spanning Breakpoint Sequences

Map of the Agnostically Identified Motif Within Breakpoint Sequences

Introduction Translocations involving the KMT2A gene (also known as MLL) are frequently diagnosed in pediatric acute leukemia cases with either lymphoblastic or myeloid origin. KMT2A is translocated to multiple partner genes, including MLLT10/AF10 localizing at chromosomal band 10p12. KMT2A‐MLLT10 is one of the common chimeric genes diagnosed in ac...

Chromosomal rearrangements of the MLL gene are responsible for 5-10% of all acute leukemias, biphenotypic leukemias and myelodysplastic syndromes. The large number of known MLL fusions (>80) renders a precise diagnosis a demanding task. Even though all MLL rearrangements are associated with high-risk acute leukemia, the outcome (poor or very poor)...

Rearrangements of the mixed lineage leukemia gene (MLL, re-named KMT2A) result in aggressive leukemia. Current risk stratification of MLL-rearranged (MLL-r) leukemia is directed by the fusion partner gene and, increasingly, by minimal residual disease (MRD) assessment after induction therapy. The clinical significance of quantifying fusion transcri...

We present a case of an infant who developed pro-B acute lymphoblastic leukemia with a rare and complex MLL-translocation. Cytogenetic analysis of bone marrow cells at diagnosis showed a 46,XY,t(X;11)(p11.2;q23)[13]/46,XY[7] karyotype. Fluorescence in situ hybridization analysis using a break apart specific probes showed a split in the MLL gene. Lo...

We present a leukemia case that exhibits a chromosomal translocation t(11;16)(q23;q23), which results in the expression of a novel KMT2A fusion gene. This novel fusion, KMT2A‐USP10, was found in a relapse of acute myeloid leukaemia M5a. USP10 belongs to a protein family that deubiquitinates a distinct set of target proteins, and thus, increases the...

Mixed lineage leukemia (MLL) gene rearrangements characterize approximately 70% of infant and 10% of adult and therapy-related leukemia. Conventional clinical diagnostics, including cytogenetics and fluorescence in situ hybridization (FISH) fail to detect MLL translocation partner genes (TPG) in many patients. Long-distance inverse (LDI)-PCR, the “...

Elucidation of activation mechanisms governing protein fusions is essential for therapeutic development. MLL undergoes rearrangement with numerous partners, including a recurrent translocation fusing the epigenetic regulator to a cytoplasmic RAS effector, AF6/afadin. We show here that AF6 employs a non-canonical, evolutionarily conserved α-helix to...

We describe the case of a boy with acute myeloid leukemia with translocation t(6;11)(p22.2;q23) and insertion ins(11;9)(q23;p21.3p21.3). Translocation t(6;11)(p22.2;q23) involving the short arm of chromosome 6 has not been previously described. The LDI-PCR showed the presence of KMT2A-MLLT3 fusion and identified the BTN3A1 (butyrophilin subfamily 3...

Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here, we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified....

In pediatric acute myeloid leukemia (AML), chromosomal abnormalities leading to a disruption of the lysine methyltransferase 2A (KMT2A) gene in 11q23 are the most frequent rearrangements. Here, we report on the identification of a novel cryptic insertion, ins(11;X)(q23;q28q12), resulting in a translocation of the KMT2A gene in 11q23, leading to a K...

Chromosomal translocations involving 11q23, resulting in rearrangements of the mixed lineage leukemia gene (MLL, re-named KMT2A) are frequent events in childhood leukemia. MLL is highly promiscuous, with approximately 80 fusions now characterized. Although fluorescence in situ hybridization (FISH) has high specificity for detecting MLL-rearrangemen...

Introduction Acute lymphoblastic leukaemia (ALL) in infants has poor overall survival despite being characterized by very few genetic aberrations per case. The most common genetic change, present in over 75% of cases, is the rearrangement of the mixed lineage leukaemia (MLL/KMT2A) gene (MLL-R) that also occurs in AML and mixed phenotype acute leuka...

IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in childhood B-cell precursor acute lymphoblastic leukemia. Because of its clinical importance, we previously mapped breakpoints of intragenic deletions and developed a multiplex PCR assay to detect recurrent intragenic ΔIKZF1. Since the multiplex PCR was not able to detect complete delet...

In pediatric acute leukemias, reciprocal chromosomal translocations frequently cause gene fusions involving the lysine (K)-specific methyltransferase 2A gene (KMT2A, also known as MLL). Specific KMT2A fusion partners are associated with the disease phenotype (lymphoblastic vs. myeloid), and the type of KMT2A rearrangement also has prognostic implic...

Aim. To evaluate the relation between genomic DNA breakpoints in MLL and translocation partner genes (TPG) and clinical parameters of infant AL. Methods. 68 infants (29 boys and 39 girls with median age of 4.8 mo) with MLL-rearranged acute lymphoblastic leukemia (ALL) (n = 46), acute myeloid leukemia (AML) (n = 20) and mixed phenotype acute leukemi...

We describe a unique case of a woman with acute myeloid leukemia with a new, previously undescribed translocation, t(11;18)(q23;q21.2), affecting the KMT2A (MLL) gene and resulting in an KMT2A(MLL)-ME2 fusion. This disease occurred secondarily following chemotherapy for a different acute myeloid leukemia with the recurrent genetic abnormality inv(1...

We have investigated patients with Ikaros deletions (IKZF1Δ) at 7p12. IKZF1Δ mutations are correlated with a differentiation block in normal B-cell devlopment and frequently diagnosed in preB cell ALL and BCR-ABL+ ALL leukemia patients. Here, we focussed on the analysis of patients with whole gene deletions of IKZF1. Our preliminary results demonst...

Rearrangements of the mixed-lineage leukemia gene (MLL, the Drosophila trithorax homolog) are important and generally adverse prognostic factors in hematological diseases [1]. However, they appear to involve different biological mechanisms, as suggested by their diversity, their different distribution in acute lymphoblastic leukemia (ALL) versus ac...

Purpose: While 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...

Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal instability disorder characterized by a high incidence of pediatric hematologic malignancies. Majority of patients affected are of Slavic origin and share the same founder mutation of 657del5 within the NBN gene encoding protein involved in DNA double-strand breaks (DSB) repair....

Secondary acute lymphoblastic leukemia (sALL) following chemotherapy and/or radiotherapy of previous malignancies represents 2–10% of all cases of ALL. A 72-year-old female patient was diagnosed with acute lymphoblastic leukemia following chemotherapy for a diffuse large B cell lymphoma. Banding cytogenetics showed a t(t(5;11)(q23–31;q23) in 20 of...