Deubiquitinases: Pro-oncogenic Activity and Therapeutic Targeting in Acute Leukemia

Gutierrez Diaz, Blanca Teresa

doi:https://doi.org/10.21985/n2-jdzg-1x35

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Deubiquitinases: Pro-oncogenic Activity and Therapeutic Targeting in Acute Leukemia

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Chemotherapy regimens show high response rates but have debilitating effects and carry risk of relapse. Until now, no targeted therapy has been approved. In addition, 40% of patients will relapse and their treatment options are limited because of lack of alternatives. Thus, development of non-toxic, specific treatments for relapsed T-ALL patients is an unmet clinical need.Glucocorticoids (GCs) are essential components of ALL treatment, administered to patients in all the different phases of therapy. Nevertheless, glucocorticoid response is variable and T-ALL patients often show resistance to these drugs. Glucocorticoid resistance is associated to an increased risk of relapse and poor clinical outcome. However, the mechanisms underlying resistance are not completely understood and this represents an important challenge to improve patient prognosis. The lymphocyte cell-specific protein-tyrosine kinase (LCK) is an essential component of the T cell receptor (TCR) signaling pathway, important for T cell activation. Interestingly, it is known that glucocorticoids can attenuate TCR signaling and in turn, hyperactivation of LCK is correlated to glucocorticoid resistance in T-ALL patients. The interplay between TCR and GC-signaling seems to affect response to glucocorticoids, but the mechanisms underlying this phenomenon remain obscure. Recent work has showed that deubiquitinases or DUBs participate in various pathways related to leukemogenesis, disease maintenance and therapy response in mice and humans. Moreover, the dependency of these hematological malignancies on certain DUBs renders them as excellent candidates for putative targeted therapy. This thesis explores and elaborates on the role of deubiquitination in T-ALL development, response to glucocorticoid treatment and its potential as candidates for targeted therapy in this population. Our work found that the ubiquitin-specific protease 7 (USP7) is highly expressed and necessary for cell growth under in vitro and in vivo T-ALL systems. USP7 also showed to be present at higher levels in high-risk patients when compared to medium and low risk cases. Further analysis found that USP7 interacts and forms a complex with LCK. Interestingly, LCK deubiquitination by USP7 and its partner, USP11, did not affect protein stability but instead controlled LCK activity, altering downstream TCR signaling. Impairment of LCK activity also led to increased expression of the glucocorticoid receptor (GR), an important component in the GC-signaling transduction pathway, culminating into transcriptional activation of proapoptotic factors, including BCL2L11 or Bim, and enhanced response to glucocorticoids. In summary, this work unveils how disturbances on the ubiquitination system affect signaling pathways leading to cancer survival and drug resistance, suggesting that DUBs can be novel therapeutic targets and their inhibition could be used in combination with already existing therapies to treat leukemia patients with bad or poor prognosis.

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