Novel therapeutic strategies for MLL-rearranged leukemias

Wong, Nok-Hei Mickey; So, Chi Wai Eric

doi:10.1016/j.bbagrm.2020.194584

Cited by 14 publications

(18 citation statements)

References 262 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Unfortunately, the relation of metabolic profile with genetic mutations was not investigated further. Rearrangement of the MLL gene is one of the major driver mutations in acute leukemia (AML and acute lymphoid leukemia (ALL)), accounting for up to 10% of cases across all age groups [30]. MLL-rearrangement is an independent poorer prognostic factor in both ALL and AML [31], but the most common MLL/AF9 mutation in AML only indicates an intermediate prognosis [30,32].…”

Section: Discussionmentioning

confidence: 99%

“…Rearrangement of the MLL gene is one of the major driver mutations in acute leukemia (AML and acute lymphoid leukemia (ALL)), accounting for up to 10% of cases across all age groups [30]. MLL-rearrangement is an independent poorer prognostic factor in both ALL and AML [31], but the most common MLL/AF9 mutation in AML only indicates an intermediate prognosis [30,32]. However, elderly patients aged over 60 years old still show a dismal remission rate in response to induction chemotherapy and a disappointing 5-year overall survival; therefore, they would benefit from more effective and less toxic therapeutics.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

High Metabolic Dependence on Oxidative Phosphorylation Drives Sensitivity to Metformin Treatment in MLL/AF9 Acute Myeloid Leukemia

Liu

Patnana

Xie

et al. 2022

Cancers

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) is a group of hematological cancers with metabolic heterogeneity. Oxidative phosphorylation (OXPHOS) has been reported to play an important role in the function of leukemic stem cells and chemotherapy-resistant cells and are associated with inferior prognosis in AML patients. However, the relationship between metabolic phenotype and genetic mutations are yet to be explored. In the present study, we demonstrate that AML cell lines have high metabolic heterogeneity, and AML cells with MLL/AF9 have upregulated mitochondrial activity and mainly depend on OXPHOS for energy production. Furthermore, we show that metformin repressed the proliferation of MLL/AF9 AML cells by inhibiting mitochondrial respiration. Together, this study demonstrates that AML cells with an MLL/AF9 genotype have a high dependency on OXPHOS and could be therapeutically targeted by metformin.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

High Metabolic Dependence on Oxidative Phosphorylation Drives Sensitivity to Metformin Treatment in MLL/AF9 Acute Myeloid Leukemia

Liu

Patnana

Xie

et al. 2022

Cancers

View full text Add to dashboard Cite

show abstract

“…The MLL gene is a frequent target of rearrangement in human leukemia, especially in infant and pediatric leukemia [9,19,20]. It is well established that the rearrangement heralds poor prognosis [5,21]. These rearrangements include fusions with many partner genes, but rarely involve the X chromosome.…”

Section: Discussionmentioning

confidence: 99%

MLL-SEPT6 Positive Acute Myeloid Leukemia Patients Often Co-occur With NRAS Mutations?

Chen

2021

Preprint

View full text Add to dashboard Cite

BackgroundThe MLL-SEPT6 fusion gene is a relatively rare genetic event in leukemia. Its clinical characteristics, prognosis, especially the profile of co-occurring gene mutations remain unclear. MethodsWe retrospectively analyzed four rare leukemia cases carrying MLL-SEPT6 in our hospital from laboratory examination, diagnosis, treatment and prognosis, and provided a comprehensive and detailed description on clinical profile of MLL-SEPT6-positive AML patients in the literature. ResultsAll the four patients were diagnosed with acute myeloid leukemia (AML) and harbored X chromosome and 11 chromosome rearrangements. Three of four cases occurred NRAS mutation while the rest one with congenital AML did not. Of the four cases, one developed drug-resistant, one suffered relapse after bone marrow transplantation (BMT) and one died. Combined with other cases reported in literatures, we found that of all patients diagnosed with AML, 90.9% were children (≤ 9 years old) and 54.5% were infants (≤1 year old). The survival time between infant group (≤1 year old) and pediatric group (>1 and <18 years old), patients that received BMT and that received chemotherapy alone did not show significant differences (P>0.05). ConclusionsMLL-SEPT6 was more commonly observed in pediatric AML patients, some of which may co-occur with NRAS mutations. The prognosis was inconclusive and may not be related to age or BMT. More information needs to be accumulated and summarized from additional cases to confirm the underlying connection between NRAS mutations and MLL-SEPT6 in order to better understand the profile in MLL-SEPT6-positive AML.

show abstract

“…The development of therapeutic strategies to specifically inhibit the recurrent fusion proteins may also be an opportunity, as previously reviewed ( Steinhilber and Marschalek, 2018 ). Other promising options are based on the use of epigenetic drugs, such as demethylating agents and histone deacetylase inhibitors ( Wong and So, 2020 ). Additionally, immunotherapy and the inhibition of PARP ( Fritz et al, 2021 ) have shown potential to enhance the efficacy of other therapies and to ultimately overcome KMT2A -r acute leukemia.…”

Section: Introductionmentioning

confidence: 99%

Novel Diagnostic and Therapeutic Options for KMT2A-Rearranged Acute Leukemias

et al. 2022

View full text Add to dashboard Cite

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 detection of any KMT2A-r. Here we use a machine learning model to unravel the most appropriate markers for prediction of KMT2A-r in various types of acute leukemia. A Random Forest and LightGBM classifier was trained to predict KMT2A-r in patients with acute leukemia. Our results revealed a set of 20 genes capable of accurately estimating KMT2A-r. The SKIDA1 (AUC: 0.839; CI: 0.799–0.879) and LAMP5 (AUC: 0.746; CI: 0.685–0.806) overexpression were the better markers associated with KMT2A-r compared to CSPG4 (also named NG2; AUC: 0.722; CI: 0.659–0.784), regardless of the type of acute leukemia. Of importance, high expression levels of LAMP5 estimated the occurrence of all KMT2A-USP2 fusions. Also, we performed drug sensitivity analysis using IC50 data from 345 drugs available in the GDSC database to identify which ones could be used to treat KMT2A-r leukemia. We observed that KMT2A-r cell lines were more sensitive to 5-Fluorouracil (5FU), Gemcitabine (both antimetabolite chemotherapy drugs), WHI-P97 (JAK-3 inhibitor), Foretinib (MET/VEGFR inhibitor), SNX-2112 (Hsp90 inhibitor), AZD6482 (PI3Kβ inhibitor), KU-60019 (ATM kinase inhibitor), and Pevonedistat (NEDD8-activating enzyme (NAE) inhibitor). Moreover, IC50 data from analyses of ex-vivo drug sensitivity to small-molecule inhibitors reveals that Foretinib is a promising drug option for AML patients carrying FLT3 activating mutations. Thus, we provide novel and accurate options for the diagnostic screening and therapy of KMT2A-r leukemia, regardless of leukemia subtype.

show abstract

Novel therapeutic strategies for MLL-rearranged leukemias

Cited by 14 publications

References 262 publications

High Metabolic Dependence on Oxidative Phosphorylation Drives Sensitivity to Metformin Treatment in MLL/AF9 Acute Myeloid Leukemia

High Metabolic Dependence on Oxidative Phosphorylation Drives Sensitivity to Metformin Treatment in MLL/AF9 Acute Myeloid Leukemia

MLL-SEPT6 Positive Acute Myeloid Leukemia Patients Often Co-occur With NRAS Mutations?

Novel Diagnostic and Therapeutic Options for KMT2A-Rearranged Acute Leukemias

Contact Info

Product

Resources

About