Biology subjects

Diaz-Munoz, M. D.

Publications and source records attributed to Diaz-Munoz, M. D..

4 recordsLinked to original sources

bioRxiv2026

A PTBP1-CDC42 splicing axis regulates leukemia growth and venetoclax sensitivity in acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive blood cancer characterized by high rates of relapse and poor outcomes, especially in elderly or unfit patients, who cannot tolerate intensive chemotherapy. While the BCL2 inhibitor venetoclax has improved initial responses in this high-risk population, relapses remain nearly universal, highlighting the need for novel therapeutic strategies. Here, we identify the RNA-binding protein PTBP1 as a critical dependency in AML. PTBP1 depletion impairs leukemic growth in vitro and in vivo, and is associated with widespread splicing alterations and global disruption of protein synthesis. Integrative transcriptomic and iCLIP analyses reveal that PTBP1 orchestrates a splicing program centered on Rho GTPase signaling, with CDC42 as a key downstream effector. Mechanistically, PTBP1 loss triggers a splicing switch from CDC42-v1 to CDC42-v2, leading to reduced GTPase activity and impaired protein synthesis. Pharmacological inhibition of CDC42 selectively induces cytotoxicity in AML cells, while sparing healthy hematopoietic cells. Importantly, CDC42 inhibition markedly enhances venetoclax anti-leukemic efficacy. These findings establish PTBP1 as a critical regulator of AML cell fitness and identify a clinically actionable therapeutic combination that exploits AML dependency on PTBP1-CDC42 signaling to enhance the efficacy of venetoclax-based regimens.

cancer biology↗

bioRxiv2024

Post-transcriptional control of homeostatic B- cell signalling by HuR is required for innate B cell maintenance and function.

Innate B-1 cells constitute a self-maintained layer of defence for early detection of bacteria, clearance of apoptotic cell debris and removal of autoantigens driving autoimmunity. B-1 cells are originated from foetal tissues but, as opposed to B-2 cells, the molecular mechanisms behind their development and homeostatic maintenance remain largely unknown. Here we demonstrate that post-transcriptional regulation by the RNA binding protein HuR is essential for the homeostatic self-replenishment of innate B-1 cells, the expansion of B-1 cell clones targeting self-antigens and the production of natural autoantibodies. HuR KO B-1 cells fail to express the high levels of surface BCR, TACI and BAFFR required for tonic signalling and cell survival. Mechanistically, HuR binds to the 3UTRs of mRNAs encoding these surface receptors and of pro-survival molecules, like BCL-2 and MCL-1, promoting their translation into protein. In summary, we reveal the need of post-transcriptional regulation in BCR expression, tonic signalling and homeostatic maintenance of functional B-1 cells.

immunology↗

bioRxiv2024

Post-transcriptional regulation by TIA1 and TIAL1 controls the transcriptional program enforcing T cell quiescence.

Immune protection against new and recurrent infections relies on long-term maintenance of a highly diversified T-cell repertoire. Transcription factors cooperate to enforce T-cell metabolic quiescence and maintenance. However, less is known about the post-transcriptional networks that preserve peripheral naive T cells. Here we describe the RNA binding proteins TIA1 and TIAL1 as key promoters of CD4 and CD8 T cell quiescence. T cells deficient in TIA1 and TIAL1 undergo uncontrolled cell proliferation in the absence of cognate antigens, leading this to a premature T-cell activation, exhaustion and death. Mechanistically, TIA1 and TIAL1 control the expression of master regulatory transcription factors, FOXP1, LEF1 and TCF1, that restrain homeostatic T-cell proliferation. In summary, our study highlights a previously unrecognised dependency on post-transcriptional gene regulation by TIA1 and TIAL1 for implementing the quiescent transcriptional programs for long survival of T cells.

immunology↗

bioRxiv2018

Alternative translation initiation generates a functionally distinct isoform of the stress-activated kinase MK2

Shaping of the proteome by alternative translation is an important mechanism of post-transcriptional gene regulation. It can lead to the expression of multiple protein isoforms originating from the same mRNA. Here we show that a novel, abundant and long isoform of the stress/p38MAPK-activated kinase MK2, a key regulator of transcription, migration, death signaling and post-transcriptional gene regulation, is constitutively translated from an alternative CUG translation initiation start site located in the 5'UTR of its mRNA. GC-rich sequences and putative G-quadruplex structures influence the usage of that codon as a translation initiation start site and the RNA helicase eIF4A1 is needed to ensure alternative isoform translation. We recapitulated the usage of the alternative start codon and determined the molecular properties of the short and a long MK2 isoforms. Phenotypically, only the short isoform phosphorylated Hsp27, supported migration and stress-induced immediate early gene (IEG) expression. Interaction profiling by quantitative mass-spectrometry revealed short isoform-specific binding partners that were associated with migration. In contrast, the long isoform contains additional putative phosphorylation sites in its unique N-terminus. In sum, our data reveal a longer and previously non-described isoform of MK2 with distinct physiological properties originating from alternative translation.

molecular biology↗