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BIOMARKER:

MLL translocation

i
Other names: HTRX1, HTRX, MLL1A, Mixed Lineage Leukemia 1, Myeloid/Lymphoid Or Mixed-Lineage Leukemia Protein 1, CXXC7, MLL1, TRX1, Zinc Finger Protein HRX, Trithorax-Like Protein, ALL-1, Lysine (K)-Specific Methyltransferase 2A, CXXC-Type Zinc Finger Protein 7, Histone-Lysine N-Methyltransferase 2A, Myeloid/Lymphoid Or Mixed-Lineage Leukemia, Lysine Methyltransferase 2A, MLL, Myeloid/Lymphoid Or Mixed-Lineage Leukemia, KMT2A
17d
Furthermore, the results of a meta‑analysis using Heuser's AML dataset supported the finding that chemotherapy responders have higher expression levels of HOXA11. These results indicated that the expression of HOXA11 increased cell apoptosis and predicted an improved response to Ara‑C in AML.
Journal
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KRAS (KRAS proto-oncogene GTPase) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • KMT2A (Lysine Methyltransferase 2A) • RELA (RELA Proto-Oncogene)
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MLL translocation
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cytarabine
18d
In patients with complex karyotypes, the microarray analysis made a significant contribution toward the accurate characterization of chromosomal defects. In summary, our results show that the integration of multiple investigative strategies increases the detection yield of genetic defects with potential clinical relevance.
Clinical • Journal • Next-generation sequencing
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FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • KMT2A (Lysine Methyltransferase 2A)
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NPM1 mutation • MLL translocation • DNMT3A R882
18d
However, emerging evidences suggest that the methyltransferase activity of KMT2 enzymes can also be important in cancer, raising the prospect of targeting the catalytic domain of KMT2 as a therapeutic strategy. In this review, we summarize recent advances in our understanding of KMT2 enzyme mechanisms and their regulation on nucleosomes, which will provide mechanistic insights into therapeutic discoveries targeting their methyltransferase activities.
Review • Journal
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KMT2A (Lysine Methyltransferase 2A)
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MLL translocation
1m
Conditional deletion of Tip60 prevented the development of MLL-AF10 and MLL-ENL leukemia, indicating that Tip60 is indispensable for the leukemogenic activity of the MLL-AF10 and MLL-ENL-fusions. Our findings provide novel insight about epigenetic regulation in the development of MLL-AF10 and MLL-ENL-fusion leukemia.
Journal
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KMT2A (Lysine Methyltransferase 2A) • HOXA9 (Homeobox A9) • MEIS1 (Meis Homeobox 1) • MLLT1 (MLLT1 Super Elongation Complex Subunit)
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MLL translocation • MLL fusion
2ms
Proximity-based labeling using biotin ligase is a novel approach for identifying proteins that interact with CALM-AF10. Among the candidates we identified, EPS15 and CTTN are known to bind to CRM1 and are involved in signal transduction and transcriptional regulation. Our demonstration that they also directly interact with CALM-AF10 suggests a potential role in CALM-AF10 leukemogenesis.
IO biomarker
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EGFR (Epidermal growth factor receptor) • KMT2A (Lysine Methyltransferase 2A) • NUP214 (Nucleoporin 214) • DOT1L (DOT1 Like Histone Lysine Methyltransferase)
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MLL translocation
8ms
Results : As of June 2020, 25 pts with ALL were enrolled and received VEN + CTx; CTx regimens included dexamethasone and/or vincristine and/or peg-asparaginase (D/V/P, n=16) or cytarabine and/or etoposide and/or peg-asparaginase (C, n=9). Our genomic profiling suggests that responses with VEN + CTx occur in pediatric ALL with a variety of mutations, including those with KMT2A rearrangements. However, due to the limited sample size and the overall heterogeneity, further investigation in a larger pt cohort is warranted to determine which mutations confer resistance or sensitivity to VEN.
Clinical • Combination therapy • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • RB1 (RB Transcriptional Corepressor 1) • MCL1 (Myeloid cell leukemia 1) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • KMT2D (Lysine Methyltransferase 2D) • BCL2L1 (BCL2-like 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • CREBBP (CREB binding protein)
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KMT2D mutation • MLL rearrangement • RB1 mutation • BCL2 expression • PTPN11 mutation • MCL1 expression • MLL translocation • PDGFRB mutation
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Venclexta (venetoclax) • cytarabine • etoposide IV • vincristine
8ms
Conclusions : Our first assessment of risk alleles for cytogenetic subsets of AML identified two novel independent risk loci associated with 11q23/KMT2A-translocated AML, and one risk locus associated with CBF-AML. These data suggest an important, subtype-specific role for transcriptional elongation in AML and that functional studies of retro transposition elements should be undertaken in leukemogenesis.
Retrospective data
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NPM1 (Nucleophosmin 1) • AFF1 (AF4/FMR2 Family Member 1)
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NPM1 mutation • MLL translocation • Chr t(4;11)(q21;q23)
8ms
Our data suggest that a human fetal cell context plays a key role in the phenotypic and genotypic features of MLL-AF4+ iALL. We also show proof of principle evidence that our fetal CRISPRMLL-AF4+ model is a powerful tool for addressing mechanistic questions about MLL-AF4 function and provides an important platform for identifying and testing novel therapies.
CD19 (CD19 Molecule) • CD34 (CD34 molecule)
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MLL translocation • MLL fusion
8ms
Very late relapses, defined as relapse occurring >5 years after complete remission, are rare, accounting for 1% to 3% of relapses. We describe a patient with AML harboring an AFDN/KMT2A translocation who relapsed 12 years after matched sibling stem cell transplant, provide a brief review of the relevant literature, and describe proposed mechanisms to explain very late relapse AML.
Clinical • Journal
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MLL translocation
8ms
Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with R/R AML. A phase II trial of iadademstat in combination with azacitidine is ongoing (EudraCT No.: 2018-000482-36).
P1 data • Journal
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MLL rearrangement • MLL translocation
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azacitidine • iadademstat (ORY-1001)
9ms
In leukemias that clinically and/or immunophenotypically mimic APL, identification of specific gene translocations can lead to the correct diagnosis and may carry therapeutic/prognostic implications.
Clinical • Journal
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MLL translocation
9ms
Overall, this study demonstrates for the first time profound activity of the menin-MLL1 inhibitor as a single agent in clinically relevant PDX models of leukemia. These data provide a strong rationale for clinical translation of MI-3454 or its analogs for leukemia patients with MLL1-rearrangements or NPM1 mutations.
Clinical • Journal
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NPM1 (Nucleophosmin 1) • MEIS1 (Meis Homeobox 1)
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NPM1 mutation • MLL rearrangement • MLL translocation
10ms
S-adenosylmethionine (SAM) as the universal methyl donor in human cells serves as substrate for many important methyltransferases like H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) or protein arginine methyltransferase 5 (PRMT5) maintaining MLLr leukemogenesis... In summary, our data highlight that MAT2A plays a key role in MLLr cell survival and accentuate the therapeutic potential of MAT2A inhibition. We thereby established the preclinical rationale to target MAT2A in leukemia patients harboring MLL translocations.
CD34 (CD34 molecule) • PRMT5 (Protein Arginine Methyltransferase 5)
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MLL rearrangement • MLL translocation
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Adomet (S-adenosyl-L-methionine)
10ms
Proliferation and the impact of FFAR2 antagonist GLPG0974 were determined by Trypan blue staining... In summary, our study highlights the feasibility of engineering chromosomal translocations at their endogenous loci in human HSPCs derived from both huCB and huBM to generate pure MLLr cells as innovative and authentic human leukemia model. Further, we show that MLL-AF4 is unable to transform HSPCs derived from huBM cells indicating an important role of the fusion partner and the cell of origin. Mechanistically, downregulation of FFAR2 seems to be mandatory for leukemia development.
CD34 (CD34 molecule)
|
MLL rearrangement • MLL translocation
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GLPG0974
10ms
Proliferation and the impact of FFAR2 antagonist GLPG0974 were determined by Trypan blue staining... In summary, our study highlights the feasibility of engineering chromosomal translocations at their endogenous loci in human HSPCs derived from both huCB and huBM to generate pure MLLr cells as innovative and authentic human leukemia model. Further, we show that MLL-AF4 is unable to transform HSPCs derived from huBM cells indicating an important role of the fusion partner and the cell of origin. Mechanistically, downregulation of FFAR2 seems to be mandatory for leukemia development.
CD34 (CD34 molecule)
|
MLL rearrangement • MLL translocation
|
GLPG0974
10ms
S-adenosylmethionine (SAM) as the universal methyl donor in human cells serves as substrate for many important methyltransferases like H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) or protein arginine methyltransferase 5 (PRMT5) maintaining MLLr leukemogenesis... In summary, our data highlight that MAT2A plays a key role in MLLr cell survival and accentuate the therapeutic potential of MAT2A inhibition. We thereby established the preclinical rationale to target MAT2A in leukemia patients harboring MLL translocations.
CD34 (CD34 molecule) • PRMT5 (Protein Arginine Methyltransferase 5)
|
MLL rearrangement • MLL translocation
|
Adomet (S-adenosyl-L-methionine)
10ms
S-adenosylmethionine (SAM) as the universal methyl donor in human cells serves as substrate for many important methyltransferases like H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) or protein arginine methyltransferase 5 (PRMT5) maintaining MLLr leukemogenesis... In summary, our data highlight that MAT2A plays a key role in MLLr cell survival and accentuate the therapeutic potential of MAT2A inhibition. We thereby established the preclinical rationale to target MAT2A in leukemia patients harboring MLL translocations.
CD34 (CD34 molecule) • PRMT5 (Protein Arginine Methyltransferase 5)
|
MLL rearrangement • MLL translocation
|
Adomet (S-adenosyl-L-methionine)
10ms
Proliferation and the impact of FFAR2 antagonist GLPG0974 were determined by Trypan blue staining... In summary, our study highlights the feasibility of engineering chromosomal translocations at their endogenous loci in human HSPCs derived from both huCB and huBM to generate pure MLLr cells as innovative and authentic human leukemia model. Further, we show that MLL-AF4 is unable to transform HSPCs derived from huBM cells indicating an important role of the fusion partner and the cell of origin. Mechanistically, downregulation of FFAR2 seems to be mandatory for leukemia development.
CD34 (CD34 molecule)
|
MLL rearrangement • MLL translocation
|
GLPG0974
10ms
Proliferation and the impact of FFAR2 antagonist GLPG0974 were determined by Trypan blue staining... In summary, our study highlights the feasibility of engineering chromosomal translocations at their endogenous loci in human HSPCs derived from both huCB and huBM to generate pure MLLr cells as innovative and authentic human leukemia model. Further, we show that MLL-AF4 is unable to transform HSPCs derived from huBM cells indicating an important role of the fusion partner and the cell of origin. Mechanistically, downregulation of FFAR2 seems to be mandatory for leukemia development.
CD34 (CD34 molecule)
|
MLL rearrangement • MLL translocation
|
GLPG0974
10ms
S-adenosylmethionine (SAM) as the universal methyl donor in human cells serves as substrate for many important methyltransferases like H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) or protein arginine methyltransferase 5 (PRMT5) maintaining MLLr leukemogenesis... In summary, our data highlight that MAT2A plays a key role in MLLr cell survival and accentuate the therapeutic potential of MAT2A inhibition. We thereby established the preclinical rationale to target MAT2A in leukemia patients harboring MLL translocations.
CD34 (CD34 molecule) • PRMT5 (Protein Arginine Methyltransferase 5)
|
MLL rearrangement • MLL translocation
|
Adomet (S-adenosyl-L-methionine)
10ms
These results suggest selective serine/glycine starvation as an option for supportive leukemia treatment.
PTBP1 (Polypyrimidine Tract Binding Protein 1)
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MLL translocation • MLL fusion
11ms
This may explain why MLL rearrangements often occur before birth in human infant leukemia patients, but transformation usually does not occur until after birth, when Lin28b levels decline. Our findings show that the efficiency of MLL-ENL-driven AML initiation changes through the course of pre- and postnatal development, and developmental programs can be manipulated to impede transformation.
Preclinical • Journal
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MLL translocation • MLL fusion
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