Drug Repurposing for Targeting Acute Leukemia With KMT2A (MLL)—Gene Rearrangements

Tsakaneli, Alexia; Williams, Owen

doi:10.3389/fphar.2021.741413

Cited by 10 publications

(8 citation statements)

References 137 publications

(168 reference statements)

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“…New treatment strategies are urgently needed for both KMT2A/MLL-R + AML and KMT2A/MLL-R + ALL. Therefore, a large panel of drugs are being evaluated as potential therapeutic agents against KMT2A/MLL-R + AML and ALL, including inhibitors of Menin-MLL1 interaction [25][26][27][28] . The present study demonstrates that PTK inhibitors (PTKi), especially inhibitors of FLT3, may have clinical impact potential as therapeutic agents against KMT2A/MLL-R + B-ALL as well as AML.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine kinases in KMT2A/MLL-rearranged acute leukemias as potential therapeutic targets to overcome cancer drug resistance

Uçkun¹,

Qazi²

2022

Cancer Drug Resist

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Aim: The main goal of this study was to elucidate at the transcript level the tyrosine kinase expression profiles of primary leukemia cells from mixed lineage leukemia 1 gene rearranged (KMT2A/MLL-R+) acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. Methods: We evaluated protein tyrosine kinase (PTK) gene expression profiles of primary leukemic cells in KMT2A/MLL-R+ AML and ALL patients using publicly available archived datasets. Results: Our studies provided unprecedented evidence that the genetic signatures of KMT2A/MLL-R+ AML and ALL cells are characterized by transcript-level overexpression of specific PTK. In infants, children and adults with KMT2A/MLL-R+ ALL, as well as pediatric patients with KMT2A/MLL-R+ AML, the gene expression levels for FLT3, BTK, SYK, JAK2/JAK3, as well as several SRC family PTK were differentially amplified. In adults with KMT2A/MLL-R+ AML, the gene expression levels for SYK, JAK family kinase TYK2, and the SRC family kinases FGR and HCK were differentially amplified. Conclusion: These results provide new insights regarding the clinical potential of small molecule inhibitors of these PTK, many of which are already FDA/EMA-approved for other indications, as components of innovative multi-modality treatment platforms against KMT2A/MLL-R+ acute leukemias.

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Section: Discussionmentioning

confidence: 99%

Tyrosine kinases in KMT2A/MLL-rearranged acute leukemias as potential therapeutic targets to overcome cancer drug resistance

Uçkun¹,

Qazi²

2022

Cancer Drug Resist

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“…In terms of prognosis, several studies have shown that all MLL -r AML should be classified into the poor prognosis group regardless of TPGs[ 3 , 4 , 13 ], and the WBC count at diagnosis, achieving complete remission after the first course of treatment, and transplantation are independent risk factors in multivariate analysis[ 7 , 8 , 9 , 25 ]. The effects of immunotherapy and inhibitors targeting MLL-r acute leukemia need to be further explored[ 16 , 26 - 29 ]. We could not observe any therapeutic effects because the patient died soon after diagnosis.…”

Section: Discussionmentioning

confidence: 99%

t(4;11) translocation in hyperdiploid de novo adult acute myeloid leukemia: A case report

Zhang¹,

Zhao²,

Zhang³

2022

World J Clin Cases

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BACKGROUND MLL gene rearrangement is a common genetic abnormality of acute myeloid leukemia (AML), which predicts poor prognosis and is important in clinical diagnosis. MLL rearrangement involves many chromosomes, among which, t(4;11) translocation is rare in AML. The present case was t(4;11) AML, accompanied by a hyperdiploid karyotype. Such cases have not been reported previously. CASE SUMMARY An adult male with self-reported symptoms of fatigue, febrility and hyperleukocytosis was diagnosed with AML by morphology and confirmed by immunophenotype analysis. Uncommonly, chromosomal and fluorescence in situ hybridization (FISH) analysis showed a hyperdiploid karyotype with t(4;11) translocation and MLL rearrangement, and a negative MLL – AF4 fusion gene result. The patient died of respiratory and circulatory failure 5 days after diagnosis. CONCLUSION t(4;11) AML with hyperdiploid karyotype has not been reported. In this case, t(4;11) was only detected by karyotype analysis and FISH, suggesting their importance in MLL rearrangement detection.

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“…Another pharmacological efficient approach in cancer treatment might be the targeting of pathways deregulated in tumorigenesis. Indeed, the inhibition of glycogen synthase kinase 3 (GSK3) can induce the growth arrest of leukemia cells in KMT2Ar leukemia [ 78 ], while targeting the DNA damage response (DDR) pathway can lead to specific synthetic lethality in leukemic cells with MLL-rearrangements [ 79 ].…”

Section: Epigenetic Strategies For Pharmacological Approachesmentioning

confidence: 99%

KMT2A: Umbrella Gene for Multiple Diseases

Castiglioni

Fede

Bernardelli

et al. 2022

Genes

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KMT2A (Lysine methyltransferase 2A) is a member of the epigenetic machinery, encoding a lysine methyltransferase responsible for the transcriptional activation through lysine 4 of histone 3 (H3K4) methylation. KMT2A has a crucial role in gene expression, thus it is associated to pathological conditions when found mutated. KMT2A germinal mutations are associated to Wiedemann–Steiner syndrome and also in patients with initial clinical diagnosis of several other chromatinopathies (i.e., Coffin–Siris syndromes, Kabuki syndrome, Cornelia De Lange syndrome, Rubinstein–Taybi syndrome), sharing an overlapping phenotype. On the other hand, KMT2A somatic mutations have been reported in several tumors, mainly blood malignancies. Due to its evolutionary conservation, the role of KMT2A in embryonic development, hematopoiesis and neurodevelopment has been explored in different animal models, and in recent decades, epigenetic treatments for disorders linked to KMT2A dysfunction have been extensively investigated. To note, pharmaceutical compounds acting on tumors characterized by KMT2A mutations have been formulated, and even nutritional interventions for chromatinopathies have become the object of study due to the role of microbiota in epigenetic regulation.

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Drug Repurposing for Targeting Acute Leukemia With KMT2A (MLL)—Gene Rearrangements

Cited by 10 publications

References 137 publications

Tyrosine kinases in KMT2A/MLL-rearranged acute leukemias as potential therapeutic targets to overcome cancer drug resistance

Tyrosine kinases in KMT2A/MLL-rearranged acute leukemias as potential therapeutic targets to overcome cancer drug resistance

t(4;11) translocation in hyperdiploid de novo adult acute myeloid leukemia: A case report

KMT2A: Umbrella Gene for Multiple Diseases

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