scholarly journals Molecular Characterization of the Highest Risk Adult Patients with Acute Myeloid Leukemia (AML) through Multi-omics Clustering

2021 ◽  
Author(s):  
Trinh Nguyen ◽  
John W Pepper ◽  
Cu Nguyen ◽  
Yu Fan ◽  
Ying Hu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Drug Targets ◽  
Standard Of Care ◽  
Expression Data ◽  
Current Standard ◽  
Molecular Subgroup ◽  
Response To Chemotherapy ◽  
Poor Outcomes ◽  
Acute Myeloid

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.

scholarly journals Molecular characterization of the highest risk adult patients with acute myeloid leukemia (AML) through multi-omics clustering

2021 ◽  
Author(s):  
trinh nguyen ◽  
John Pepper ◽  
Cu Nguyen ◽  
Yu Fan ◽  
Ying Hu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Drug Targets ◽  
Molecular Pathways ◽  
Current Standard ◽  
Molecular Subgroup ◽  
Response To Chemotherapy ◽  
Significant Difference ◽  
Acute Myeloid

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 .

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 ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Molecular Characterization ◽  
Myeloid Leukemia ◽  
Drug Targets ◽  
Targeted Therapeutics ◽  
Molecular Subgroup ◽  
Molecular Features ◽  
Response To Chemotherapy ◽  
Acute Myeloid

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.

scholarly journals Therapeutic targeting of FLT3 and associated drug resistance in acute myeloid leukemia

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Melat T. Gebru ◽  
Hong-Gang Wang
Keyword(s):  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Gene Mutations ◽  
Standard Of Care ◽  
Cell Transplant ◽  
Current Standard ◽  
Hematopoietic Stem ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) is a heterogeneous disease caused by several gene mutations and cytogenetic abnormalities affecting differentiation and proliferation of myeloid lineage cells. FLT3 is a receptor tyrosine kinase commonly overexpressed or mutated, and its mutations are associated with poor prognosis in AML. Although aggressive chemotherapy often followed by hematopoietic stem cell transplant is the current standard of care, the recent approval of FLT3-targeted drugs is revolutionizing AML treatment that had remained unchanged since the 1970s. However, despite the dramatic clinical response to targeted agents, such as FLT3 inhibitors, remission is almost invariably short-lived and ensued by relapse and drug resistance. Hence, there is an urgent need to understand the molecular mechanisms driving drug resistance in order to prevent relapse. In this review, we discuss FLT3 as a target and highlight current understanding of FLT3 inhibitor resistance.

scholarly journals Novel Agents for Acute Myeloid Leukemia

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 429 ◽  
Author(s):  
Mario Luppi ◽  
Francesco Fabbiano ◽  
Giuseppe Visani ◽  
Giovanni Martinelli ◽  
Adriano Venditti
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Standard Of Care ◽  
Gemtuzumab Ozogamicin ◽  
Novel Agents ◽  
Current Standard ◽  
New Agents ◽  
Emerging Treatments ◽  
Approved Drugs ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a complex hematological disease characterized by genetic and clinical heterogeneity. Recent advances in the understanding of AML pathogenesis have paved the way for the development of new agents targeting specific molecules or mechanisms that contribute to finally move beyond the current standard of care, which is “3 + 7” regimen. In particular, new therapeutic options such as targeted therapies (midostaurin and enasidenib), monoclonal antibodies (gemtuzumab ozogamicin), and a novel liposomal formulation of cytarabine and daunorubicin (CPX-351) have been recently approved, and will be soon available for the treatment of adult patients with AML. In this review, we will present and describe these recently approved drugs as well as selected novel agents against AML that are currently under investigation, and show the most promising results as monotherapy or in combination with chemotherapy. The selection of these emerging treatments is based on the authors’ opinion.

scholarly journals Vosaroxin in relapsed/refractory acute myeloid leukemia: efficacy and safety in the context of the current treatment landscape

2017 ◽  
Vol 8 (6) ◽  
pp. 185-195 ◽  
Author(s):  
Valeriy Sedov ◽  
Robert K. Stuart
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Standard Of Care ◽  
Initial Response ◽  
Current Treatment ◽  
Phase Iii ◽  
Double Blind ◽  
Poor Outcomes ◽  
Acute Myeloid

Treatment for acute myeloid leukemia (AML) generally consists of a combination of cytarabine and an anthracycline. Although induction therapy leads to complete remission (CR) for most patients, refractoriness to chemotherapy or relapse after initial response is associated with poor outcomes. The 1-year survival rates after first relapse have been reported at 29%, declining to 11% at 5 years. Prognosis is particularly poor among older patients whose higher prevalence of unfavorable cytogenetics and high frequency of comorbidities diminish their ability to tolerate intensive chemotherapy. There is no standard of care for relapsed/refractory (R/R) AML, and no new therapies have shown consistently superior outcomes in this setting in over two decades. Vosaroxin is an anticancer quinolone derivative (AQD) that was evaluated in combination with cytarabine for the treatment of R/R AML in the randomized, double-blind, placebo-controlled, phase III VALOR study ( n = 711). Compared with placebo/cytarabine, the vosaroxin/cytarabine regimen demonstrated favorable CR rates and survival in patients ⩾60 years of age, with toxicities similar to other AML regimens. Here we review outcomes of recent studies of commonly used chemotherapy regimens for the treatment of R/R AML and evaluate the results of the VALOR trial in the context of the current treatment landscape.

Acute Myeloid Leukemia Genetics: Risk Stratification and Implications for Therapy

2015 ◽  
Vol 139 (10) ◽  
pp. 1215-1223 ◽  
Author(s):  
Michael L. Wang ◽  
Nathanael G. Bailey
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Clinical Presentation ◽  
Standard Of Care ◽  
Current Standard ◽  
Future Directions ◽  
Genetic Characteristics ◽  
Genetic Assessment ◽  
Acute Myeloid

Acute myeloid leukemia is a category of diseases with a common aggressive clinical presentation but with a prognosis and management that is dependent upon the underlying genetic characteristics of the neoplasm. The purpose of this brief review is to update the practicing pathologist on the current standard of care in the genetic evaluation of acute myeloid leukemia and to highlight future directions in the classification, genetic assessment, and management of these devastating diseases.

Clinical Features and Recurrence Pattern of Perianal Abscess in Patients with Acute Myeloid Leukemia

2017 ◽  
Vol 138 (1) ◽  
pp. 10-13 ◽  
Author(s):  
Hung Chang ◽  
Ming-Chung Kuo ◽  
Tzung-Chih Tang ◽  
Tung-Liang Lin ◽  
Jin-Hou Wu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Gastrointestinal Tract ◽  
Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Perianal Abscess ◽  
Standard Of Care ◽  
Recurrence Pattern ◽  
Surgical Interventions ◽  
Acute Myeloid

Introduction: Perianal abscess may develop during neutropenia periods in patients with acute myeloid leukemia (AML). The standard of care for perianal abscess in AML is unclear. Methods: We retrospectively collected patient data in our institute from 2009 to 2012. Results: Two hundred ninety-two patients with AML were analyzed. In total, 1,051 chemotherapy sessions were administered. Twenty-three patients experienced perianal abscess. Patients with perianal abscess were younger than those without (44 vs. 60 years, p < 0.0001). Perianal abscess developed in various phases of treatment and in the stem cell transplantation period. Twelve recurrences developed in 6 patients. Patients with a prior perianal abscess have a 10-fold risk of developing a subsequent abscess following further chemotherapy. The microbiology profile revealed that most pathogens were derived from the intestinal tracts, which was similar to the findings of previous studies. The 28-day mortality was 14.3% and the direct cause of death was not perianal abscess in any case. Surgical interventions had no impact on recurrence or survival. Conclusion: In patients with AML, perianal abscess results from gastrointestinal tract pathogens. Many patients do not require surgical interventions. The mortality is low but recurrence is common following subsequent chemotherapies. Therefore, awareness of recurrence is important for the timely management of perianal abscess in AML.

scholarly journals Acute myeloid leukemia with CPSF6–RARG fusion resembling acute promyelocytic leukemia with extramedullary infiltration

2021 ◽  
Vol 12 ◽  
pp. 204062072097698
Author(s):  
Xiaoyan Han ◽  
Chunxiang Jin ◽  
Gaofeng Zheng ◽  
Yi Li ◽  
Yungui Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Myeloid Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Specific Factor ◽  
Acid Receptor ◽  
Response To Chemotherapy ◽  
Acute Myeloid

Some subtypes of acute myeloid leukemia (AML) share morphologic, immunophenotypic, and clinical features of acute promyelocytic leukemia (APL), but lack a PML–RARA (promyelocytic leukemia–retinoic acid receptor alpha) fusion gene. Instead, they have the retinoic acid receptor beta (RARB) or retinoic acid receptor gamma (RARG) rearranged. Almost all of these AML subtypes exhibit resistance to all-trans retinoic acid (ATRA); undoubtedly, the prognosis is poor. Here, we present an AML patient resembling APL with a novel cleavage and polyadenylation specific factor 6 ( CPSF6) –RARG fusion, showing resistance to ATRA and poor response to chemotherapy with homoharringtonine and cytarabine. Simultaneously, the patient also had extramedullary infiltration.

scholarly journals The Expression Changes of CX3CL1 and Interlukin-6 Genes During Remission Induction Therapy in Patients With Acute Myeloid Leukemia

2021 ◽  
Vol 10 ◽  
pp. e2288
Author(s):  
Mahdiyar Iravani Saadi ◽  
Mani Ramzi ◽  
Aliasghar Karimi ◽  
Maryam Owjfard ◽  
Mahmoud Torkamani ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Hematologic Malignancy ◽  
Quantitative Polymerase Chain Reaction ◽  
Remission Induction ◽  
Response To Chemotherapy ◽  
Before And After ◽  
Acute Myeloid

Background: Acute Myeloid Leukemia syndrome (AML) is a hematologic malignancy which is due to clonal extensive proliferation of leukemic precursor cells and is rapidly fatal unless treated or response to chemotherapy. Cytogenetic findings have important role in prognosis and categorization of AML. The aim of this study was to investigate the expression changes in CX3CL1 and Interlukin-6 (IL-6) genes before and after chemotherapy as remission induction therapy in AML patients. Materials and Methods: In this study 69 patients (36 males, 33 female) with AML was selected from tertiary medical heath center. A quantitative polymerase chain reaction (PCR) was done for mRNA expression of CX3CL1 and IL-6genes before and after induction chemotherapy. To obtain expression changes in CX3CL1 and IL-6genes, we used 2-ΔΔCT method. Results: The expression of CX3CL1 and IL-6 was significantly increased after induction chemotherapy. Also, the ΔCt mean of CX3CL1 and IL-6 mRNA was not significant between AML subtype groups. Conclusion: In conclusion, as we showed that chemotherapy significantly increase the expression of CX3CL1 and IL-6 which can be used as a prognostic factor of AML.

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