scholarly journals The retinoic acid receptor co-factor NRIP1 is uniquely upregulated and represents a therapeutic target in acute myeloid leukemia with chromosome 3q rearrangements

Haematologica ◽  
2021 ◽  
Author(s):  
Sarah Grasedieck ◽  
Ariene Cabantog ◽  
Liam MacPhee ◽  
Junbum Im ◽  
Christoph Ruess ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Therapeutic Target ◽  
Myeloid Leukemia ◽  
Integration Site ◽  
Retinoic Acid Receptor ◽  
Aberrant Expression ◽  
Interacting Protein ◽  
Disease Subtype ◽  
Non Coding Rna ◽  
Acute Myeloid

Aberrant expression of Ecotropic Viral Integration Site 1 (EVI1) is a hallmark of acute myeloid leukemia (AML) with inv(3) or t(3;3), which is a disease subtype with especially poor outcome. In studying transcriptomes from AML patients with chromosome 3q rearrangements, we identified a significant upregulation of the Nuclear Receptor Interacting Protein 1 (NRIP1) as well as its adjacent non-coding RNA LOC101927745. Utilizing transcriptomic and epigenomic data from over 900 primary patient samples as well as genetic and transcriptional engineering approaches, we have identified several mechanisms that can lead to upregulation of NRIP1 in AML. We hypothesize that the LOC101927745 transcription start site harbors a context-dependent enhancer that is bound by EVI1, causing upregulation of NRIP1 in AML with chr3 abnormalities. Furthermore, we show that NRIP1 knockdown negatively affects the proliferation and survival of 3q-rearranged AML cells and increases their sensitivity towards ATRA, suggesting that NRIP1 is relevant for the pathogenesis of inv(3)/t(3;3) AML and could serve as a novel therapeutic target in myeloid malignancies with 3q abnormalities.

Aberrant Expression of Hepatocyte Growth Factor Induces Autocrine MET Activation Providing a Novel Therapeutic Target In Acute Myeloid Leukemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1042-1042
Author(s):  
Alex Kentsis ◽  
Takaomi Sanda ◽  
Vu Ngo ◽  
Scott J. Rodig ◽  
Jeffery Kutok ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Therapeutic Target ◽  
Myeloid Leukemia ◽  
Complex Karyotype ◽  
Aberrant Expression ◽  
Hepatocyte Growth ◽  
Acute Myeloid ◽  
Novel Therapeutic

Abstract Abstract 1042 Despite improvements in the treatment of acute myeloid leukemia (AML), high risk disease such as complex aberrant karyotype AML remains largely refractory to current therapy, and is mostly fatal. Identification of effective therapeutic targets by using candidate gene approaches has been limited by the number and variety of genetic defects associated with AML. Thus, we carried out a genome-wide functional screen in complex karyotype AML using a retroviral library of short hairpin RNAs (shRNAs), and discovered that shRNA-mediated depletion of hepatocyte growth factor (HGF) specifically inhibits growth of AML cells but not a panel of lymphoid cancer cells. HGF was to found to be aberrantly expressed in about 15% of patients with AML, including most patients with complex karyotype disease. In contrast to normal CD34+ cells that express MET (but not HGF), 5 of 7 cell lines derived from patients with complex karyotype AML exhibited aberrant expression of HGF that was associated with autocrine activation of its receptor MET. Depletion of HGF or MET using multiple independent shRNAs profoundly reduced proliferation and induced cell death in AML cells lines that express HGF but not those that lack HGF expression. Inhibition of MET using the tyrosine kinase inhibitor (SU11274) or HGF using neutralizing anti-HGF antibody (R&D Systems) also inhibited growth and induced apoptosis in AML cell lines dependent on HGF/MET activation but not those that lack HGF expression. Thus, aberrant HGF expression causes autocrine MET activation and oncogene dependence in a subset of patients with AML, confers sensitivity to HGF/MET inhibition, and provides a novel therapeutic target for this otherwise lethal disease. Disclosures: No relevant conflicts of interest to declare.

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 HDAC8: A Promising Therapeutic Target for Acute Myeloid Leukemia

2020 ◽  
Vol 8 ◽  
Author(s):  
Marco Spreafico ◽  
Alicja M. Gruszka ◽  
Debora Valli ◽  
Mara Mazzola ◽  
Gianluca Deflorian ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Therapeutic Target ◽  
Myeloid Leukemia ◽  
Promising Therapeutic Target ◽  
Acute Myeloid

scholarly journals Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

Blood ◽  
2015 ◽  
Vol 125 (15) ◽  
pp. 2386-2396 ◽  
Author(s):  
Francis Mussai ◽  
Sharon Egan ◽  
Joseph Higginbotham-Jones ◽  
Tracey Perry ◽  
Andrew Beggs ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Therapeutic Target ◽  
Myeloid Leukemia ◽  
Leukemia Blast ◽  
Key Points ◽  
Acute Myeloid Leukemia Blast ◽  
Acute Myeloid ◽  
Novel Therapeutic

Key Points Arginase depletion with BCT-100 pegylated recombinant human arginase is cytotoxic to AML blasts.

Sign in / Sign up

Export Citation Format

Share Document