Select microtubule inhibitors increase lysosome acidity and promote lysosomal disruption in acute myeloid leukemia (AML) cells
Abstract To identify new biological vulnerabilities in acute myeloid leukemia, we screened a library of natural products for compounds cytotoxic to TEX leukemia cells. This screen identified the novel small molecule Deoxysappanone B 7,4′ dimethyl ether (Deox B 7,4), which possessed nanomolar anti-leukemic activity. To determine the anti-leukemic mechanism of action of Deox B 7,4, we conducted a genome-wide screen in Saccharomyces cerevisiae and identified enrichment of genes related to mitotic cell cycle as well as vacuolar acidification, therefore pointing to microtubules and vacuolar (V)-ATPase as potential drug targets. Further investigations into the mechanisms of action of Deox B 7,4 and a related analogue revealed that these compounds were reversible microtubule inhibitors that bound near the colchicine site. In addition, Deox B 7,4 and its analogue increased lysosomal V-ATPase activity and lysosome acidity. The effects on microtubules and lysosomes were functionally important for the anti-leukemic effects of these drugs. The lysosomal effects were characteristic of select microtubule inhibitors as only the Deox compounds and nocodazole, but not colchicine, vinca alkaloids or paclitaxel, altered lysosome acidity and induced lysosomal disruption. Thus, our data highlight a new mechanism of action of select microtubule inhibitors on lysosomal function.
Publication date: Available online 29 May 2020Source: Clinical Lymphoma Myeloma and LeukemiaAuthor(s): Stefania Crisci, Elvira Pota, Giancarla Iaccarino, Irene Postiglione, Concetta Meo, Sara Mele, Rosaria De Filippi, Antonio Pinto
Contributors : Britta Will ; Laura Barreyro ; Daniel T StarzynowskiSeries Type : Expression profiling by arrayOrganism : Homo sapiensWe applied transcriptional analysis of multiple, highly fractionated stem and progenitor populations from patients with acute myeloid leukemia (AML) with complex karyotype. We isolated phenotypic long-term HSC (LT-HSC), short-term HSC (ST-HSC), and committed granulocyte-monocyte progenitors (GMP) from individual patients, and measured gene expression profiles of each population, and in comparison to their phenotypic counterparts from age-matched healthy controls.In this dataset, we include th...
Publication date: Available online 21 April 2020Source: Clinical Lymphoma Myeloma and LeukemiaAuthor(s): Samah Fathy Semary, Mahmoud Hammad, Sonya Soliman, Dina Yassen, Marwa Gamal, Doaa Albeltagy, Nayera Hamdy, Sonia Mahmoud
Condition: Leukemia, Myeloid Intervention: Other: Demonstration of T cell responses Sponsor: Hospices Civils de Lyon Not yet recruiting
(University of Texas M. D. Anderson Cancer Center) A combination therapy of ivosenidib (IVO) plus venetoclax (VEN) with or without azacitidine (AZA) was found to be effective against a specific genetic subtype of acute myeloid leukemia (AML) in a Phase Ib/II trial led by researchers at The University of Texas MD Anderson Cancer Center.
Publication date: 26 May 2020Source: Cell Reports, Volume 31, Issue 8Author(s): Ramprasad Ramakrishnan, Pablo Peña-Martínez, Puneet Agarwal, Maria Rodriguez-Zabala, Marion Chapellier, Carl Högberg, Mia Eriksson, David Yudovich, Mansi Shah, Mats Ehinger, Björn Nilsson, Jonas Larsson, Anna Hagström-Andersson, Benjamin L. Ebert, Ravi Bhatia, Marcus Järås
t(16;21)(q24;q22) is a rare, nonrandom chromosomal aberration first described in 1989 in a pediatric patient with ‘de novo’ acute myeloid leukemia (AML).1As a result, the RUNX1 gene, located at 21q22, fuses to the CBFA2T3 gene located at 16q24.2The RUNX1-CBFA2T3 fusion protein acts, throughout normal and neoplastic myelopoiesis, as an altered transcriptional co-repressor capable of recruiting histone deacet ylases and suppressing the expression of RUNX1 target genes.3, 4.
Conditions: Acute Myeloid Leukemia, in Relapse; Myelodysplastic Syndromes Intervention: Drug: CB-5339 Sponsor: Cleave Therapeutics, Inc. Not yet recruiting
Publication date: Available online 26 May 2020Source: Clinical Lymphoma Myeloma and LeukemiaAuthor(s): Prajwal Dhakal, Elizabeth Lyden, E Muir Kate-Lynn, Zaid S. Al-Kadhimi, Lori J. Maness, Krishna Gundabolu, Vijaya Raj Bhatt