| Autor: |
Safa FM; Section of Hematology and Medical Oncology, Deming Department of Medicine, Tulane University, New Orleans, LA., Rasmussen T; Section of Hematology and Medical Oncology, Deming Department of Medicine, Tulane University, New Orleans, LA., Fontan L; Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College., Xia M; Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College., Melnick A; Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College., Wiestner A; Hematology Branch, National Heart, Lung, and Blood Institute, NIH, NHLBI, Bethesda, MD., Lobelle-Rich P; Section of Hematology and Medical Oncology, Deming Department of Medicine, Tulane University, New Orleans, LA., Burger JA; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX., Mouawad Y; Section of Hematology and Medical Oncology, Deming Department of Medicine, Tulane University, New Orleans, LA., Safah H; Section of Hematology and Medical Oncology, Deming Department of Medicine, Tulane University, New Orleans, LA., Flemington EK; Tulane Cancer Center, Tulane University, New Orleans, LA., Saba NS; Section of Hematology and Medical Oncology, Deming Department of Medicine, Tulane University, New Orleans, LA. nsaba@tulane.edu. |
| Abstrakt: |
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. |
