scholarly journals T-LAK cell-originated protein kinase presents a novel therapeutic target inFLT3-ITD mutated acute myeloid leukemia

Oncotarget ◽  
2015 ◽  
Vol 6 (32) ◽  
pp. 33410-33425 ◽  
Author(s):  
Houda Alachkar ◽  
Martin Mutonga ◽  
Gregory Malnassy ◽  
Jae-Hyun Park ◽  
Noreen Fulton ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Protein Kinase ◽  
Therapeutic Target ◽  
Myeloid Leukemia ◽  
Lak Cell ◽  
Acute Myeloid ◽  
Novel Therapeutic

Protein Kinase CK2α as an Unfavorable Prognostic Marker and Novel Therapeutic Target in Acute Myeloid Leukemia

2007 ◽  
Vol 13 (3) ◽  
pp. 1019-1028 ◽  
Author(s):  
Jin Seok Kim ◽  
Ju In Eom ◽  
June-Won Cheong ◽  
Ae Jin Choi ◽  
Jin Koo Lee ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Protein Kinase ◽  
Prognostic Marker ◽  
Therapeutic Target ◽  
Myeloid Leukemia ◽  
Acute Myeloid ◽  
Novel Therapeutic

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.

scholarly journals EGFL7 Antagonizes NOTCH Signaling and Represents a Novel Therapeutic Target in Acute Myeloid Leukemia

2019 ◽  
Vol 26 (3) ◽  
pp. 669-678
Author(s):  
Marius Bill ◽  
Aparna Pathmanathan ◽  
Malith Karunasiri ◽  
Changxian Shen ◽  
Matthew H. Burke ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Notch Signaling ◽  
Therapeutic Target ◽  
Myeloid Leukemia ◽  
Acute Myeloid ◽  
Novel Therapeutic

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.

Inhibition of serotonin receptor type 1 in acute myeloid leukemia impairs leukemia stem cell functionality: a promising novel therapeutic target

Leukemia ◽  
2017 ◽  
Vol 31 (11) ◽  
pp. 2288-2302 ◽  
Author(s):  
A Etxabe ◽  
M C Lara-Castillo ◽  
J M Cornet-Masana ◽  
A Banús-Mulet ◽  
M Nomdedeu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Therapeutic Target ◽  
Myeloid Leukemia ◽  
Serotonin Receptor ◽  
Leukemia Stem Cell ◽  
Cell Functionality ◽  
Acute Myeloid ◽  
Novel Therapeutic

scholarly journals circMYBL2, a circRNA from MYBL2, regulates FLT3 translation by recruiting PTBP1 to promote FLT3-ITD AML progression

Blood ◽  
2019 ◽  
Vol 134 (18) ◽  
pp. 1533-1546 ◽  
Author(s):  
Yu-Meng Sun ◽  
Wen-Tao Wang ◽  
Zhan-Cheng Zeng ◽  
Tian-Qi Chen ◽  
Cai Han ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Therapeutic Target ◽  
Myeloid Leukemia ◽  
Circular Rna ◽  
Acute Myeloid ◽  
Novel Therapeutic

Sun et al identify a circular RNA, circMYBL2, that upregulates FLT3 translation to promote FLT3-ITD acute myeloid leukemia (AML) progression, suggesting a novel therapeutic target for FLT3-ITD AML.

scholarly journals Targeting NMNAT1 in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 879-879
Author(s):  
Xiangguo Shi ◽  
Daisuke Nakada ◽  
Ayumi Kitano ◽  
Rebecca Murdaugh ◽  
Yu-Jung Tseng ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Therapeutic Target ◽  
Myeloid Leukemia ◽  
Leukemia Cells ◽  
Chemotherapy Treatment ◽  
Normal Cells ◽  
Nad Biosynthesis ◽  
Acute Myeloid ◽  
Novel Therapeutic

Acute myeloid leukemia (AML) is primarily a disease of older adults with poor treatment outcomes. Despite years of intensive research, the standard induction therapy for AML has remained largely unchanged for decades. Thus, the development of new and efficacious therapeutic targets for AML is urgently needed. Leukemia cells exhibit multiple metabolic aberrations that may be therapeutically targeted. Here, we show that nicotinamide adenine dinucleotide (NAD+) promotes leukemogenesis and causes chemotherapy treatment resistance through fueling energetic metabolism, and pinpoints nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) is a novel therapeutic target for AML. To identify novel genes essential for AML, we performed a whole genome CRISPR dropout screen by using MOLM13 cell line and identified 1,951 essential genes (Fig. A). By searching druggable targets among these genes, we narrowed down to 345 genes, among which we found two genes, NMNAT1 (nicotinamide nucleotide adenylyltransferase 1) and NAMPT (nicotinamide phosphoribosyltransferase), both involved in key steps in NAD+ biosynthesis. We comprehensively analyzed dependency scores for all genes involved in the NAD+ biosynthetic pathways (de novo synthesis pathway, the Preiss-Handler pathway and the salvage pathway) across a broad panel of cancer cell lines from the Dependency Map database (https://depmap.org/portal/). The results showed that NMNAT1 and NAMPT are both strongly selective and uniquely required for hematological malignancies compared to other cancers (Fig. B). Since little success has been achieved for NAMPT inhibitors in clinical trials, our attention was drawn to NMNAT1, which encodes a nuclear localized enzyme catalyzing the final step in NAD+ biosynthesis. We confirmed that deletion of NMNAT1 in AML cells significantly reduced nuclear NAD+ level and cell viability over time while sparing normal hematopoietic progenitor cells, suggesting that NMNAT1 is targetable to AML. Overexpression of wild-type Nmnat1 but not the enzymatically inactive forms rescued NMNAT1-KO AML, indicating that the catalytic activity of NMNAT1 is required for AML. To study the role of NAD+ in AML, we first measured NAD+ levels in leukemic and normal cells, and found higher NAD+ levels in leukemia-initiating cells from a murine MLL-AF9-induced AML model compared to normal cells. Supplementation of NAD+ metabolites (NMN, NAM and NR) increased AML proliferation, enhanced glycolysis (lactate production) and oxidative phosphorylation (ATP production), resulting in chemotherapy resistance (Fig. C). Deletion of NMNAT1 sensitized AML cell to chemotherapy treatment. To study the role of NMNAT1 in leukemogenesis in vivo, we genetically deleted NMNAT1 in murine or human leukemia cells, transplanted them into recipient mice, and found that deletion of NMNAT1 reduced leukemic burden and extended leukemia-free survival (Fig. D). Finally, to reveal the molecular mechanisms underlying NMNAT1 KO-mediated cell death (increased levels of gamma-H2AX), RNA-seq and functional assay of NAD+ dependent enzymes were performed. We found that the reduction of nuclear NAD+ resulting from NMNAT1 deletion upregulated genes involved in DNA repair pathway, which may be linked to impaired PARPs and Sirtuins activity. Our findings reveal the important function of NAD+ in leukemogenesis and chemoresistance, and identify NMANT1 as a novel therapeutic target for AML. Figure Disclosures No relevant conflicts of interest to declare.

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