Precursor T-cell neoplasms are aggressive hematological malignancies that mainly affect children and result from the malignant transformation of immature lymphoblasts committed to the T-cell lineage. These tumors mainly involve the bone marrow and blood (Acute T-cell lymphoblastic leukemia, T-ALL), although less frequently they appear as mass lesions in the thymus or the lymph nodes (T-cell lymphoblastic lymphoma, T-LBL). Current treatments for T-ALL/LBL usually consist of high-dose multi-agent chemotherapy followed by hematopoietic stem cell transplantation in standard-high risk patients. Although such treatments achieve reasonable levels of initial complete responses, those patients who relapse or do not respond show poor prognosis and survival rates below 10%, mainly due to the limited availability of personalized treatments.

Regarding immunotherapy, the presence of surface markers common to both normal and tumor T-cells, as well as the subsequent fratricidal effect, significantly hampers the implementation of novel treatments in comparison with other hematological malignancies, such as B-ALL or AML. With respect to precision medicine, the only drug specifically approved for T-ALL patients is neralabine and, remarkably, its administration is not based on the presence or absence of any particular alteration so that, in many cases, the potential benefits are overwhelmed by a high toxicity and the occurrence of adverse side effects. Based on the above, it is essential to implement novel personalized treatments that demonstrate greater efficacy and are associated with reduced toxicity levels.

The development of novel personalized treatments is tightly associated with the identification of promising therapeutic targets that involve the distinctive surface proteins of tumor T lymphoblasts or the signaling pathways that are frequently deregulated in T-ALL. Specifically, identifying potential therapeutic targets represents the initial stage for the development of novel personalized treatments with greater efficacy and less toxicity. Unfortunately, the identification of potential therapeutic targets is a complex task that requires in-depth knowledge of the molecular basis underlying tumor development and in many occasions does not achieve the desired results. Although exome sequencing technologies represent a milestone for unravelling the mutational burden present in the different cancer types, the molecular cascades aberrantly induced by such alterations as well as their functional consequences often remain unexplored. As a result, the number of molecules that may become potential therapeutic targets is drastically reduced. For this reason, in recent years many efforts have been directed towards the functional characterization of those alterations that recurrently affect T-ALL patients. Ultimately, a deeper understanding of the molecular basis underlying tumor development is the gateway to the implementation of improved therapies. This is especially true for complex diseases such as precursor T-cell neoplasms, which are characterized by high levels of tumor heterogeneity and exhibit recurrent genetic alterations in more than 50 different genes.

The JAK/STAT pathway is one of the signaling pathways recurrently deregulated in a high proportion of T-ALL patients through the presence of oncogenic mutations that affect different pathway members. Such alterations promote sustained phosphorylation of the STAT proteins and constitutive activation of the JAK/STAT pathway, ultimately leading to tumor development.  Unfortunately, direct inhibition of the JAK/STAT pathway remains challenging because of two major issues. On the one hand, oncogenic mutations may affect several JAK/STAT pathway members and appear simultaneously, causing an additive effect that would require the combination of multiple inhibitors for different proteins. On the other hand, STAT proteins are transcription factors whose pharmacological inhibition is complicated in terms of druggability and specificity.

In an attempt to identify potential therapeutic targets against the leukemogenesis associated with a constitutive activation of the JAK/STAT pathway, we followed an alternative approach and focused on genes downstream of the JAK/STAT pathway. Specifically, we delved into the molecular cascades that are aberrantly induced by constitutive activation of the JAK/STAT pathway and that play a significant role in leukemogenesis. In this regard, we observed that JAK/STAT pathway oncogenic mutations are associated with an aberrant transcriptional profile and induce overexpression of the PIM1 gene. Notably, the pan-PIM inhibitor PIM447 blocks the leukemogenesis associated with different JAK/STAT pathway oncogenic mutations while reducing the activation status of c-MYC and mTOR signaling pathways, highlighting a link between the presence of JAK/STAT pathway oncogenic mutations and the overactivation of c-MYC and mTOR signaling pathways through the activity of PIM proteins.

Figure 1. Identification of PIM1 as a potential therapeutic target in T-ALL/LBL. (A) Oncogenic mutations in the JAK/STAT pathway induce constitutive phosphorylation of STAT5 which deregulates the expression of multiple genes leading to tumor development. (B) PIM1 overexpression is induced by JAK/STAT oncogenic mutations and is postulated as a potential therapeutic target for T-ALL/LBL patients. PIM1 upregulation induces the overexpression of c-MYC and mTOR signaling pathways and promotes tumor development. The JAK/STAT members that are frequently mutated in T-ALL/LBL are indicated with an asterisk (*). Schematic representation was created with BioRender.com