scholarly journals Molecular Characterization of the Highest Risk Adult Patients With Acute Myeloid Leukemia (AML) Through Multi-Omics Clustering

2021 ◽  
Vol 12 ◽  
Author(s):  
Trinh Nguyen ◽  
John W Pepper ◽  
Cu Nguyen ◽  
Yu Fan ◽  
Ying Hu ◽  
...  

Background: Acute myeloid leukemia (AML) is a clinically heterogeneous group of cancers. While some patients respond well to chemotherapy, we describe here a subgroup with distinct molecular features that has very poor prognosis under chemotherapy. The classification of AML relies substantially on cytogenetics, but most cytogenetic abnormalities do not offer targets for development of targeted therapeutics. Therefore, it is important to create a detailed molecular characterization of the subgroup most in need of new targeted therapeutics.Methods: We used a multi-omics approach to identify a molecular subgroup with the worst response to chemotherapy, and to identify promising drug targets specifically for this AML subgroup.Results: Multi-omics clustering analysis resulted in three primary clusters among 166 AML adult cancer cases in TCGA data. One of these clusters, which we label as the high-risk molecular subgroup (HRMS), consisted of cases that responded very poorly to standard chemotherapy, with only about 10% survival to 2 years. The gene TP53 was mutated in most cases in this subgroup but not in all of them. The top six genes over-expressed in the HRMS subgroup included E2F4, CD34, CD109, MN1, MMLT3, and CD200. Multi-omics pathway analysis using RNA and CNA expression data identified in the HRMS subgroup over-activated pathways related to immune function, cell proliferation, and DNA damage.Conclusion: A distinct subgroup of AML patients are not successfully treated with chemotherapy, and urgently need targeted therapeutics based on the molecular features of this subgroup. Potential drug targets include over-expressed genes E2F4, and MN1, as well as mutations in TP53, and several over-activated molecular pathways.

2021 ◽  
Author(s):  
Trinh Nguyen ◽  
John W Pepper ◽  
Cu Nguyen ◽  
Yu Fan ◽  
Ying Hu ◽  
...  

Abstract Background: Acute myeloid leukemia (AML) is a clinically heterogeneous group of diseases with poor outcomes that are partly due to its complex and poorly understood heterogeneity. Methods: Here, we use a multi-omics approach to identify a molecular subgroup with the worst response to chemotherapy, and to identify promising drug targets specifically for this AML subgroup. Results: Multi-omics clustering analysis using RNA and CNA expression data resulted in the three primary clusters of 166 AML adult TCGA cancer cases. One of these clusters, which we label as the high-risk molecular subgroup (HRMS), consisted of cases that responded very poorly to standard chemotherapy, with only about 10% survival to two years. The gene TP53 was mutated in most cases in the HRMS, but not in other cases. The top 6 genes over-expressed in the HRMS included E2F4, CD34, CD109, MN1, MMLT3, and CD200. Multi-omics pathway analysis using RNA and CNA expression data identified in the HRMS subgroup over-expressed pathways related to immune function, cell proliferation, and DNA damage. Conclusion: Some AML patients are not successfully treated with the current standard of care chemotherapy, and urgently need targeted therapeutics. Potential drug targets include over-expressed genes E2F4, and MN1, as well as mutations in TP53, and several molecular pathways.


2021 ◽  
Author(s):  
trinh nguyen ◽  
John Pepper ◽  
Cu Nguyen ◽  
Yu Fan ◽  
Ying Hu ◽  
...  

Abstract Background: Acute myeloid leukemia (AML) is a clinically heterogeneous group of diseases with poor outcomes that are partly due to its complex and poorly understood heterogeneity. Methods: Here, we use a multi-omics approach to identify a molecular subgroup with the worst response to chemotherapy, and to identify promising drug targets specifically for this AML subgroup. Results: Among the three primary clusters of 166 AML adult TCGA cancer cases, we found a High Risk Molecular Subgroup with the worst overall survival at two years – only about 10% survival. TP53 was mutated in most patients in this High Risk Molecular Subgroup , but not in any other patients, constituting a highly significant difference. The top 5 Genes over-expressed in the High Risk Molecular Subgroup included E2F4, CD34, CD109, MN1, and MMLT3. This High Risk Molecular Subgroup also showed higher activation than other patients of molecular pathways related to immune function, cell proliferation, and DNA damage. Conclusion: Some AML patients are not successfully treated with the current standard of care chemotherapy, and urgently need targeted therapeutics. Potential drug targets include over-expressed genes E2F4 , and MN1 , as well as mutations in TP53, and several molecular pathways .


2016 ◽  
Vol 47 (8) ◽  
pp. 656-667 ◽  
Author(s):  
Francianne Gomes Andrade ◽  
Elda Pereira Noronha ◽  
Gisele Dallapicola Brisson ◽  
Filipe dos Santos Vicente Bueno ◽  
Ingrid Sardou Cezar ◽  
...  

2005 ◽  
Vol 75 (3) ◽  
pp. 185-192 ◽  
Author(s):  
Lene Hyldahl Olesen ◽  
Charlotte Guldborg Nyvold ◽  
Anni Aggerholm ◽  
Jan Maxwell Norgaard ◽  
Per Guldberg ◽  
...  

2014 ◽  
Vol 7 (1) ◽  
pp. 47 ◽  
Author(s):  
Tereza Jancuskova ◽  
Radek Plachy ◽  
Lucie Zemankova ◽  
David Hardekopf ◽  
Jiri Stika ◽  
...  

2021 ◽  
Vol 23 (2) ◽  
Author(s):  
Shannon E. Conneely ◽  
Alexandra M. Stevens

Abstract Purpose of Review Acute myeloid leukemia (AML) in children remains a challenging disease to cure with suboptimal outcomes particularly when compared to the more common lymphoid leukemias. Recent advances in the genetic characterization of AML have enhanced understanding of individualized patient risk, which has also led to the development of new therapeutic strategies. Here, we review key cytogenetic and molecular features of pediatric AML and how new therapies are being used to improve outcomes. Recent Findings Recent studies have revealed an increasing number of mutations, including WT1, CBFA2T3-GLIS2, and KAT6A fusions, DEK-NUP214 and NUP98 fusions, and specific KMT2A rearrangements, which are associated with poor outcomes. However, outcomes are starting to improve with the addition of therapies such as gemtuzumab ozogamicin and FLT3 inhibitors, initially developed in adult AML. Summary The combination of advanced risk stratification and ongoing improvements and innovations in treatment strategy will undoubtedly lead to better outcomes for children with AML.


Author(s):  
Nicoleta P. Berbec ◽  
Sorina M.F. Papuc ◽  
Andreea C.D.F. Tutulan-Cunita ◽  
Silvana M. Angelescu ◽  
Anca I. Lupu ◽  
...  

Leukemia ◽  
2019 ◽  
Vol 34 (3) ◽  
pp. 811-820 ◽  
Author(s):  
Luise Hartmann ◽  
Niroshan Nadarajah ◽  
Manja Meggendorfer ◽  
Alexander Höllein ◽  
Calogero Vetro ◽  
...  

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