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Profiling the activity of the para-caspase MALT1 in B-cell acute lymphoblastic leukemia for potential targeted therapeutic application.
- Source :
-
Haematologica [Haematologica] 2024 May 01; Vol. 109 (5), pp. 1348-1358. Date of Electronic Publication: 2024 May 01. - Publication Year :
- 2024
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Abstract
- B-cell acute lymphoblastic leukemia (B-ALL) remains a hard-to-treat disease with a poor prognosis in adults. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a para-caspase required for B-cell receptor (BCR)-mediated NF-κB activation. Inhibition of MALT1 in preclinical models has proven efficacious in many B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma and diffuse large B-cell lymphoma. We sought to examine the role of MALT1 in B-ALL and determine the biological consequences of its inhibition. Targeting MALT1 with both Z-VRPR-fmk and MI-2 efficiently kills B-ALL cells independent of the cell-of-origin (pro, pre, mature) or the presence of the Philadelphia chromosome, and spares normal B cells. The mechanism of cell death was through apoptotic induction, mostly in cycling cells. The proteolytic activity of MALT1 can be studied by measuring its ability to cleave its substrates. Surprisingly, with the exception of mature B-ALL, we did not detect cleavage of MALT1 substrates at baseline, nor after proteasomal inhibition or following activation of pre-BCR. To explore the possibility of a distinct role for MALT1 in B-ALL, independent of signaling through BCR, we studied the changes in gene expression profiling following a 24-hour treatment with MI-2 in 12 B-ALL cell lines. Our transcriptome analysis revealed a strong inhibitory effect on MYC-regulated gene signatures, further confirmed by Myc protein downregulation, concomitant with an increase in the Myc degrader FBXW7. In conclusion, our evidence suggests a novel role for MALT1 in B-ALL through Myc regulation and provides support for clinical testing of MALT1 inhibitors in B-ALL.
- Subjects :
- Humans
Apoptosis
Caspases metabolism
Cell Line, Tumor
Gene Expression Profiling
Molecular Targeted Therapy
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma metabolism
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein metabolism
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein antagonists & inhibitors
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein genetics
Neoplasm Proteins genetics
Neoplasm Proteins metabolism
Neoplasm Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1592-8721
- Volume :
- 109
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Haematologica
- Publication Type :
- Academic Journal
- Accession number :
- 37767562
- Full Text :
- https://doi.org/10.3324/haematol.2023.283178