Júlia Aguadé Gorgorió

• PhD
• PostDoc Position at University of California, Los Angeles

Oncogenic fusion transcription factors (TFs) frequently drive hematopoietic malignancies by altering gene expression in key developmental programs. TCF3::HLF is a fusion TF that characterizes a rare, treatment-resistant subtype of B-cell acute lymphoblastic leukemia (t(17;19) TCF3::HLF-positive B-ALL). Despite its clinical significance, the mechani...

The processes that govern human haematopoietic stem cell (HSC) self-renewal and engraftment are poorly understood and challenging to recapitulate in culture to reliably expand functional HSCs1–3. Here we identify MYC target 1 (MYCT1; also known as MTLC) as a crucial human HSC regulator that moderates endocytosis and environmental sensing in HSCs. M...

Hematopoietic stem cells (HSC) sustain life-long blood production and have the ability to recapitulate the hematopoietic system upon transplantation. This makes them therapeutically invaluable for the treatment of hematopoietic malignancies and genetic disorders. However, the regulatory processes governing HSC functional competence and engraftment...

Hematopoietic stem cells (HSC) integrate diverse environmental cues to balance between quiescence, self-renewal and differentiation. However, the molecular programs governing HSC stemness become dysregulated during culture, compromising HSC self-renewal and engraftment ability. Despite recent advances, our ability to expand functional human HSCs in...

The MLLT3 is a critical regulator of human hematopoietic stem cell (HSC) self-renewal. Analysis of RNA-seq data and epigenetic marks associated with MLLT3 gene in human HSCs uncovered a novel short MLLT3 isoform (MLLT3-S) that is expressed from a second TSS. MLLT3-S was predicted to encode a truncated protein that retains the C-terminal AHD domain...

The ontogeny of human haematopoietic stem cells (HSCs) is poorly defined owing to the inability to identify HSCs as they emerge and mature at different haematopoietic sites¹. Here we created a single-cell transcriptome map of human haematopoietic tissues from the first trimester to birth and found that the HSC signature RUNX1⁺HOXA9⁺MLLT3⁺MECOM⁺HLF⁺...

Hematopoietic stem cells (HSC) need to integrate multiple environmental cues to maintain the balance between quiescence, self-renewal and differentiation through life. During culture however, HSC self-renewal and engraftment ability become severely compromised, hindering our ability to manipulate and expand functional HSCs for therapeutic use. To u...

Despite major advances in the treatment of patients with acute lymphoblastic leukemia in the last decades, refractory and/or relapsed disease remains a clinical challenge, and relapsed leukemia patients have an exceedingly dismal prognosis. Dysregulation of apoptotic cell death pathways is a leading cause of drug resistance; thus, alternative cell...

Despite rapid progress in genomic profiling in acute lymphoblastic leukemia (ALL), identification of actionable targets and prediction of response to drugs remains challenging. To identify specific vulnerabilities in ALL, we performed a drug screen using primary human ALL samples cultured in a model of the bone marrow microenvironment combined with...

Background Hematopoietic stem cells (HSCs) are rare undifferentiated cells that, due to their ability to engraft, self‐renew and generate all blood lineages, represent a life‐saving therapy for hematopoietic malignancies and hereditary blood disorders. However, expansion of HSCs in vitro has had limited success thus far, and represents a bottleneck...

The spleen tyrosine kinase (SYK) and ζ-associated protein of 70 kD (ZAP70) tyrosine kinases play critical roles in proximal signal transduction of B-cell (BCR) and T-cell receptors (TCR), respectively. The highly similar SYK and ZAP70 kinases share a common structure composed of two tandem SH2 domains and a carboxy-terminal kinase domain. A linker...

The identification of molecular determinants that regulate sensitivity to specific agents is essential for the development of new therapeutic approaches in cancer. We have earlier shown that a subset of refractory acute lymphoblastic leukaemia (ALL) samples respond to SMAC-mimetic (SM) induced IAP depletion by concurrently inducing RIP1-dependent a...

CRISPR-Cas9 based knockout strategies are increasingly used to analyze gene function. However, redundancies and overlapping functions in biological signaling pathways can call for generating multi-gene knockout cells, which remains a relatively laborious process. Here we detail the application of multi-color LentiCRISPR vectors to simultaneously ge...

Chromosomal rearrangements of the Mixed Lineage Leukemia (MLL/KMT2A) gene leading to oncogenic MLL-fusion proteins occur in about 10% of acute leukemias and are associated with poor clinical outcomes, emphasizing the need for new treatment modalities. Inhibition of the DOT1-like histone H3K79 methyltransferase (DOT1L) is a specific therapeutic appr...

The understanding of cell death mechanisms is crucial for the development and application of novel anti-cancer therapies to avoid or circumvent drug-resistance in refractory malignancies. Impairment of apoptotic cell death plays a major role in therapy resistance and relapse of acute lymphoblastic leukemia (ALL) patients. Therefore, efforts are bei...

Dysregulation of apoptosis constitutes a general mechanism for refractory acute lymphoblastic leukemia (ALL) to escape cell death during chemotherapy. We have assessed the potential of SMAC mimetic compounds (SM) to eradicate drug resistant ALL by blocking the pro-survival cellular inhibitor of apoptosis proteins (cIAPs). On the basis of a large xe...

More precise treatment strategies are urgently needed to decrease toxicity and improve outcomes for treatment-refractory leukemia. We used ex vivo drug response profiling of high-risk, relapsed, or refractory acute lymphoblastic leukemia (ALL) cases and identified a subset with exquisite sensitivity to small-molecule mimetics of the second mitochon...

Dysregulation of apoptotic pathways provides an indiscriminate mechanism for refractory acute lymphoblastic leukemia (ALL) to escape cell death induced by many chemotherapeutic compounds. Here we have assessed the potential of SMAC mimetic (SM) compounds to short circuit cell death resistance by blocking the pro-survival cellular inhibitor of apopt...