CApSiZing T-cell acute lymphoblastic leukemia

In this issue of Hematologica, Cardoso et al. identify CASZ1 as a novel player in T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological malignancy with a high risk of relapse and associated long-term complications.¹ Thus, discovering new factors involved in the development of leukemia will enhance our basic understanding of the pathophysiology of this disease and may lead to the identification of novel therapeutic targets for T-ALL treatment. In this context, it is noteworthy that CASZ1 is particularly enriched in patients expressing elevated levels of TA L1, a well described major oncogene in T-ALL.²

CASZ1, the mammalian homolog of the Drosophila zinc finger transcription factor Castor, is known for its critical role in vascular and neural development.^3,4 CASZ1 consists of two alternatively spliced isoforms (CASZ1a and CASZ1b) which, however, seem to play similar roles. Interestingly, embryonic deletion of Casz1 leads to abnormal heart development and lethality in mice.⁵ Moreover, the potential role of CASZ1 in cancer is complex. Caren et al. first showed that the loss of several genes in the chromosome region 1p36, particularly CASZ1 and PIK3CD, is associated with the development of neuroblastoma.⁶ This initial discovery sparked a cascade of investigations into the diverse roles of CASZ1 across various cancer types and physiological processes. Beyond its tumor suppressor role in neuroblastoma, where CASZ1 low expression also significantly correlates with poor clinical outcomes,⁷ it has been shown that overexpression of CASZ1 is associated with metastasis in ovarian cancer,⁸ highlighting its potential tissue-specific role in cancer development.

In the present study, the authors start dissecting the role of CASZ1 in T-ALL by examining its interplay with key oncogenes and T-ALL-specific mutations. Taking advantage of the BloodSpot database, they found that the CASZ1b isoform (which shows higher evolutionarily conservation than CASZ1a), was significantly upregulated in T-ALL cell lines and patient samples. Interestingly, CASZ1b upregulation was especially marked in cases with high TA L1 expression, suggesting that TA L1 might regulate CASZ1b. Indeed, TA L1 overexpression or knockdown in different human T-ALL cell lines led to upregulation or downregulation of CASZ1b, respectively. Moreover, the authors found that TAL1 directly binds to the CASZ1b promoter, further reinforcing the positive correlation between TA L1 and CASZ1 in T-ALL. Still, CASZ1 was generally overexpressed in T-ALL compared to normal T cells, suggesting that additional mechanisms might be involved in the regulation of CASZ1 in TAL1-negative T-ALL cases and, more broadly, supporting a relevant role for CASZ1 in T-ALL overall. Next, the authors demonstrate that CASZ1 overexpression is sufficient to confer interleukin (IL)-3-independent growth in the otherwise IL-3-dependent Ba/F3 murine pro-B cell line, suggesting a pro-oncogenic role for CASZ1. In order to dissect the underlying mechanism, the authors performed gene expression profiling analyses in this setting and found that CASZ1 correlated with overexpression of the PI3K-AKT-mTOR signaling axis, which is well known to play a critical role in T-ALL.⁹ Notably, pharmacological inhibition of the PI3K/mTOR pathway rescued the oncogenic effects driven by CASZ1 in Ba/F3 cells, both in vitro and in vivo. Similarly, CASZ1 also positively correlates with the PI3K-AKT pathway in T-ALL cells, underscoring the central role of the PI3K/AKT/ mTOR pathway downstream of CASZ1. Still, how might CASZ1 contribute to regulating the PI3K-AKT pathway remains a key lingering question.

Building upon these findings, the authors next used a zebrafish model of NOTCH1-induced T-ALL to demonstrate that CASZ1 not only accelerated thymic hyperplasia but also actively promoted the development of NOTCH1-induced leukemia in vivo. Next, the authors performed a variety of experiments in human T-ALL cell lines in vitro in order to investigate the functional relevance of CASZ1. Under normal conditions, overexpressing CASZ1 had no impact on the viability or proliferation of human T-ALL cells. However, under stress conditions such as serum starvation, CASZ1 overex-pression displayed a prosurvival role. Moreover, CASZ1 also conferred resistance to a variety of chemotherapeutic drugs commonly used in T-ALL treatment, such as daunorubicin, dexamethasone or L-asparaginase, suggesting a broader protective role from different types of cellular stress. Finally, although CASZ1 levels did not stand out as an independent prognostic factor in newly diagnosed cases of T-ALL, high levels of CASZ1 were associated with poorer prognosis in patients with relapsed T-ALL.

Figure 1.CASZ1 effects in T-cell acute lymphoblastic leukemia.

Overall, this report uncovers a previously unknown oncogenic role for CASZ1 in T-ALL, which might be of particular relevance in the response to common anti-leukemic drug treatments and in the progression of (heavily pretreated) relapsed T-ALL cases. Thus, further studies are warranted to investigate the potential role of CASZ1 as a novel therapeutic target in T-ALL treatment.

Footnotes

• Received December 22, 2023
• Accepted January 9, 2024

Correspondence

D. Herranz dh710@cinj.rutgers.edu

Disclosures

No conflicts of interest to disclose.

Contributions

KM and DH contributed equally.

Funding

Work in the laboratory of DH is supported by The Leukemia & Lymphoma Society (Scholar Award 1386-23). KM is supported by a Fellowship from the New Jersey Commission on Cancer Research (COCR24PRF011).