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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
6d
MLL-SEPT5 Fusion Transcript in Myelodysplastic Syndrome Patient With t(11;22)(q23;q11). (PubMed, Front Med (Lausanne))
Although the MLL-SEPT5 fusion transcript was occasionally described in acute myeloid leukemia, it was first identified in MDS. Patients with MLL-SEPT5 fusion gene exhibited a poor prognosis even with an aggressive treatment.
Clinical • Journal
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KMT2A (Lysine Methyltransferase 2A)
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MLL rearrangement • MLL translocation
2ms
Phase 1/2, Open-Label, Dose Escalation, Dose Expansion Study of Menin Inhibitor DSP-5336 in Adult Patients (pts) with Acute Leukemia with and without Mixed-Lineage Leukemia (MLL )-Rearrangement or Nucleophosmin 1 (NPM1 ) Mutation (ASH 2021)
Patients on the strong CYP3A4 inhibitors ketoconazole, itraconazole, or isavuconazole, are excluded unless they can be safely taken off these medications or switched to another antifungal medication at least 7 days prior to start of study treatment. Bayesian monitoring of responses will be started after the first 10 enrolled patients are evaluable for efficacy. Study endpoints are summarized in Table 1.
Clinical • P1/2 data
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)
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NPM1 mutation • MLL rearrangement • MLL rearrangement • MLL translocation • MLL fusion
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itraconazole • DSP-5336 • ketoconazole
2ms
Database-Guided Analysis for Immunophenotypic Diagnosis and Follow-Up of Acute Myeloid Leukemia With Recurrent Genetic Abnormalities. (PubMed, Front Oncol)
This method excluded AML associated with the following genetic abnormalities: t(8;21), t(15;17), inv(16), and KMT2A translocation, with 92% sensitivity [95% confidence interval (CI): 78.6%-98.3%] and a 98.5% negative predictive value (95% CI: 90.6%-99.8%). Our data showed that the Compass database-guided analysis could identify phenotypic differences between AML groups, representing a useful tool for the identification of DfN patterns.
Journal
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KMT2A (Lysine Methyltransferase 2A)
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MLL translocation • Chr t(15;17)
2ms
Outcomes of Venetoclax and Hypomethylating Agents (HMA) in Adult Patients with KMT2A-Rearranged Leukemias (ASH 2021)
Criteria for inclusion were a pathologically confirmed diagnosis of AML, age > 18 years, treatment with either decitabine or azacitidine in combination with venetoclax. In contrast to what has been reported for chemotherapy outcomes and in the ELN classification, the KMT2A-MLLT3 translocation was not associated with improved outcomes when compared to other KMT2A translocations. While this study was limited in being retrospective and having a small and heterogeneous population, our findings suggest that venetoclax and HMA are effective in KMT2A rAML and warrant further investigation.
Clinical
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KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • KMT2A (Lysine Methyltransferase 2A) • AFF1 (AF4/FMR2 Family Member 1) • MLLT3 (MLLT3 Super Elongation Complex Subunit) • MLLT10 (MLLT10 Histone Lysine Methyltransferase DOT1L Cofactor)
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KRAS mutation • NRAS mutation • MLL rearrangement • KMT2A rearrangement • MLL translocation • MLL fusion
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Venclexta (venetoclax) • azacitidine • decitabine
2ms
Impact of the MLL Breakpoint on the Development of MLL-Rearranged Leukemia (ASH 2021)
In conclusion, we were able to establish novel human leukemia models harboring MLL-AF4 and MLL-AF9 rearrangements with different MLL breakpoints. Our models can be used to further analyze the epigenetic, transcriptomic and metabolic mechanisms underlying the poor outcome of patients suffering from MLL r leukemia.
KIT (KIT proto-oncogene, receptor tyrosine kinase) • KMT2A (Lysine Methyltransferase 2A) • CD123 (Interleukin 3 Receptor Subunit Alpha) • CD34 (CD34 molecule) • CD14 • CD9 • FCGR2A (Fc fragment of IgG receptor IIa) • DOT1L (DOT1 Like Histone Lysine Methyltransferase) • FCGR2B (Fc Fragment Of IgG Receptor IIb)
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MLL rearrangement • MLL rearrangement • MLL translocation • KMT2A expression
3ms
Aberrant Transcriptional Regulation in Development and Malignancies - Live Q&A (ASH 2021)
The protein-protein interaction between menin and Mixed Lineage Leukemia 1 (MLL1) protein plays a critical role in defective gene regulation in acute leukemia with MLL1 translocations or with mutations in the nucleophosmin 1 (NPM1) gene. Dr. Grembecka will discuss the activity of small molecule inhibitors of the menin-MLL1 interaction in AML models, including patient-derived xenograft models derived from AML primary samples. The presentation will address single agent activity and combinatorial treatments with menin inhibitors and transcriptional changes induced by these compounds in AML models.
NPM1 (Nucleophosmin 1) • ETS1 (ETS Proto-Oncogene 1)
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NPM1 mutation • MLL translocation
4ms
Significance of the MLL breaking point in the development of MLL-rearranged leukemia (DGHO 2021)
In summary, we were able to establish novel human leukemia models harboring MLL-AF4 and MLL-AF9 rearrangements with different MLL breakpoints. Our models can be used to further analyze the epigenetic, transcriptomic and metabolic mechanisms underlying the poor outcome of MLL r leukemia patients.
KIT (KIT proto-oncogene, receptor tyrosine kinase) • KMT2A (Lysine Methyltransferase 2A) • CD34 (CD34 molecule) • CD14
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MLL rearrangement • MLL translocation
5ms
Discovery of DDO-2213 as a Potent and Orally Bioavailable Inhibitor of the WDR5-Mixed Lineage Leukemia 1 Protein-Protein Interaction for the Treatment of MLL Fusion Leukemia. (PubMed, J Med Chem)
Compound 63 selectively inhibited MLL histone methyltransferase activity and the proliferation of MLL translocation-harboring cells. Furthermore, 63 displayed good pharmacokinetic properties and suppressed the growth of MV4-11 xenograft tumors in mice after oral administration, first verifying the in vivo efficacy of targeting the WDR5-MLL1 PPI by small molecules.
Journal
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WDR5 (WD Repeat Domain 5)
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MLL rearrangement • MLL translocation • MLL fusion
7ms
Discovery of M-1121 as an Orally Active Covalent Inhibitor of Menin-MLL Interaction Capable of Achieving Complete and Long-Lasting Tumor Regression. (PubMed, J Med Chem)
M-1121 is orally bioavailable and shows potent antitumor activity in vivo with tumor regressions observed at tolerated doses in the MV4;11 subcutaneous and disseminated models of MLL-rearranged leukemia. Together, our findings support development of an orally active covalent menin inhibitor as a new therapy for MLLr leukemia.
Journal
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HOXA9 (Homeobox A9) • MEIS1 (Meis Homeobox 1)
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MLL rearrangement • MLL rearrangement • MLL translocation
7ms
The intrinsically disordered proteins MLLT3 (AF9) and MLLT1 (ENL) - multimodal transcriptional switches with roles in normal hematopoiesis, MLL fusion leukemia, and kidney cancer. (PubMed, J Mol Biol)
MLLT1 undergoes phase separation to enhance recruitment of the super elongation complex (SEC) and drive transcription. Mutations in MLLT1 observed in Wilms tumor patients enhance phase separation and transcription to drive an aberrant gene expression program.
Review • Journal
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BCOR (BCL6 Corepressor) • MLLT3 (MLLT3 Super Elongation Complex Subunit) • DOT1L (DOT1 Like Histone Lysine Methyltransferase) • MLLT1 (MLLT1 Super Elongation Complex Subunit)
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MLL mutation • MLL translocation • MLL fusion
8ms
HOXA11 plays critical roles in disease progression and response to cytarabine in AML. (PubMed, Oncol Rep)
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) • KMT2A (Lysine Methyltransferase 2A) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • RELA (RELA Proto-Oncogene)
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MLL translocation
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cytarabine
8ms
Delineation of Molecular Lesions in Acute Myeloid Leukemia Patients at Diagnosis: Integrated Next Generation Sequencing and Cytogenomic Studies. (PubMed, Genes (Basel))
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
8ms
Biochemical perspectives on targeting KMT2 methyltransferases in cancer. (PubMed, Trends Pharmacol Sci)
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
8ms
Tip60 activates Hoxa9 and Meis1 expression through acetylation of H2A.Z, promoting MLL-AF10 and MLL-ENL acute myeloid leukemia. (PubMed, Leukemia)
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
9ms
[VIRTUAL] CHARACTERIZING PROTEINS THAT MEDIATE CALM-AF10 LEUKEMOGENESIS (ASPHO 2021)
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
1year
[VIRTUAL] Pediatric Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia Harboring Heterogeneous Genomic Profiles Respond to Venetoclax in Combination with Chemotherapy (ASH 2020)
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 • RB1 mutation • MLL rearrangement • BCL2 expression • PTPN11 mutation • MCL1 expression • MLL translocation • PDGFRB mutation
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Venclexta (venetoclax) • cytarabine • etoposide IV • vincristine
1year
[VIRTUAL] Meta-Analysis of Genome-Wide Association Studies of Acute Myeloid Leukemia (AML) Patients Identifies Variants Associated with Risk of 11q23/KMT2A-Translocated and Core-Binding Factor (CBF) AML and Suggests a Role for Transcription Elongation in Leukemogenesis (ASH 2020)
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)
1year
[VIRTUAL] A Novel Human Fetal Model of CRISPR-Cas9-Induced MLL-AF4 Leukemia Faithfully Recapitulates Infant ALL and Can be Used to Unravel MLL-AF4 Function (ASH 2020)
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
1year
Very Late Relapse in Pediatric Acute Myeloid Leukemia: A Case Report and Brief Literature Review. (PubMed, J Pediatr Hematol Oncol)
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
1year
First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia. (PubMed, J Clin Oncol)
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)
over1year
Monocytic Acute Myeloid Leukemias with KM2TA Translocations to Chromosome 17q that May Clinically Mimic Acute Promyelocytic Leukemia. (PubMed, Lab Med)
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
over1year
Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia. (PubMed, J Clin Invest)
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
over1year
[VIRTUAL] MAT2A promotes MLLr leukemogenesis and serves as a therapeutic target structure (DGHO 2020)
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)
over1year
[VIRTUAL] Only embryonic hematopoietic stem cells from umbilical cord blood can be brought to malignant progression by MLL-AF4 translocations (DGHO 2020)
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)
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MLL rearrangement • MLL translocation
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GLPG0974
over1year
[VIRTUAL] Only embryonic hematopoietic stem cells from umbilical cord blood can be brought to malignant progression by MLL-AF4 translocations (DGHO 2020)
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)
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MLL rearrangement • MLL translocation
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GLPG0974
over1year
[VIRTUAL] MAT2A promotes MLLr leukemogenesis and serves as a therapeutic target structure (DGHO 2020)
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)
over1year
[VIRTUAL] MAT2A promotes MLLr leukemogenesis and serves as a therapeutic target structure (DGHO 2020)
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
|
Adomet (S-adenosyl-L-methionine)
over1year
[VIRTUAL] Only embryonic hematopoietic stem cells from umbilical cord blood can be brought to malignant progression by MLL-AF4 translocations (DGHO 2020)
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
over1year
[VIRTUAL] Only embryonic hematopoietic stem cells from umbilical cord blood can be brought to malignant progression by MLL-AF4 translocations (DGHO 2020)
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
over1year
[VIRTUAL] MAT2A promotes MLLr leukemogenesis and serves as a therapeutic target structure (DGHO 2020)
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
|
Adomet (S-adenosyl-L-methionine)
over1year
[VIRTUAL] Can We Starve Leukemia? Metabolic needs of the MLL (DGHO 2020)
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
over1year
The efficiency of murine MLL-ENL-driven leukemia initiation changes with age and peaks during neonatal development. (PubMed, Blood Adv)
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