Patients most often present with signs of bone marrow failure, such as anemia, neutropenia and thrombocytopenia, manifesting as recurrent and possibly life-threatening infections, fatigue, fever, pallor and frequent bleeding. In the setting of CNS involvement, which is restricted to advanced stages of the disease, symptoms including headaches, lethargy and cranial nerve palsies may be seen. Clinical examination may reveal splenomegaly and lymphadenopathy [14].

The initial diagnosis can be made based on laboratory findings that reveal anemia and thrombocytopenia, with either a low or high leukocyte count, but very low neutrophil levels. If pleural effusions are suspected during physical examination, either radiography or CT may be performed to exclude the presence of a mass in the mediastinum. Because bone marrow is the primary site of involvement, a biopsy with subsequent immunophenotyping through flow cytometry is the mainstay of diagnosis. Diffuse infiltration of the marrow by lymphoblasts is a typical feature of T-ALL, while markers of T-cell are CD1a, CD2, CD3, CD4, CD5, CD7 and CD8.

High-dose aggressive chemotherapy with methotrexate, a folate analog that inhibits enzymes requiring folic acid, is the mainstay of T-ALL therapy [7]. This drug is given in doses of 20 mg/m2 per os every week or by 24-hour intravenous infusion in doses of 33.6 g/m2 [7]. Although the optimal dose of the drug has yet to be agreed upon [7].

Because NOTCH1 mutations have been identified in a large number of patients, directed therapy against receptor activity in the form of γ-secretase inhibitors (GSIs) showed promising results in initial studies [4].

Unfortunately, mutations that make the tumor resistant to GSIs have been discovered and the exact circumstances under which these mutations occur remain to be disclosed [13]. Nelarabine, a T-cell cytotoxic drug, was added to the regimen in patients with a poor prognosis and did not prolong survival rates in a significant manner, but it did reduce the rate of neutropenic infections [8].

Various factors have been proposed as prognostic markers, including high T-cell count (> 100x10^9/L), older age (> 35 years) and female gender [12]. Recent introduction of aggressive chemotherapy has shown to be curative in over 75% of children and in 5% of adults [4], but despite all therapeutic measures, approximately 15% of pediatric and 40% of adult patients suffer a relapse of the disease, primarily due to acquired therapy resistance [9]. More devastating is the fact that 5-year overall survival rates for adult patients are only 45% despite reaching remission, which points to a highly malignant and invasive nature of this disease [10]. On the other hand, the prognosis is somewhat better in the pediatric population, in whom long-term mortality rates are 20% [11].

Malignant T-lymphocytes in T-ALL arise from hematopoietic progenitor cells that further develop into partially proliferated thymocytes as a result of numerous genetic mutations and alterations [4] [6]. Some of the most important mutations that have been identified include [4] [5] [6].:

• T cell oncogenes such as HOX11, TAL1, LYL1, LMO1, and LMO2.
• Inactivation of the CDKN2A/INK4A/ARF and p14/16 Tumor suppressor gene.
• LIM-only domain (LMO) genes, LMO1 and LMO2.
• Upregulation of NOTCH1 transmembrane receptors.

In approximately 40% of patients suffering from this malignant disease, chromosomal aberrations that are responsible T-ALL development remain unknown [3].

ALL is considered to be the most frequently diagnosed malignant disease in children and T-ALL is responsible for approximately 15% of pediatric and 25% of adult cases, respectively [1] [12]. Numerous reports show a significant predilection toward male patients [4], while additional risk factors are currently not established.

Dysregulated production of thymocytes is influenced by numerous genes. In up to 60% of cases, mutations in NOTCH1 are observed. The NOTCH family of protein transmembrane receptors are crucial for regulation of apoptosis, cell proliferation and their fate during development. Aberrant signalling mediated by these receptors has been established in many other tumors, not only T-ALL [13]. Mutations in LCK, tumor suppressor genes (CDKN2A/INK4A/ARF) and transcription factors have been identified in many patients as well [6]. Several T-cell oncogenes, including HOX11, TAL1, LYL1, LMO1, and LMO2 have shown abnormal expression in the setting of T-ALL and their roles in influencing proper thymocyte development have been well-established [5].

Although the pathogenesis of T-ALL is partly understood, prevention of genetic events that lead to its development remains impossible. Certain risk factors for leukemias, in general, such as environmental exposure to benzene, ionizing radiation and lifestyle habits including smoking and obesity [15]., could be acted upon, but current preventive strategies for this type of malignancy do not exist.

T-cell acute lymphoblastic leukemia (T-ALL) is a variant of acute lymphoblastic leukemia, which is considered as the most common malignancy of childhood, comprising almost 10-15% of all cancers seen in the pediatric population [1]. It is estimated that 15% of all ALLs in the pediatric population are T-ALL, whereas the ratio in adults rises up to 25% [2]. T-ALL stems from hematopoietic progenitor cells that are set for T-cell development and it is thought that partially developed thymocytes are, in fact, the source of this malignancy [3] [4]. The pathogenesis model is complex, involving various mutations of T-cell oncogenes, tumor suppressor genes, transcription factors and proteins involved in signal transduction, the end-result being disruption of normal thymocyte proliferation [5] [6]. Mutations of NOTCH1, a family of transmembrane protein receptors involved in transcription and regulation of cellular signalling, are present in about 60% of cases [4]. In 40% of patients, however, the exact cause remains unknown [3]. This tumor is seen more commonly in males and the diagnosis mandates a high index of clinical suspicion based on findings obtained during physical examination and laboratory studies. Bone marrow failure is observed in virtually all patients, manifesting as fatigue, recurrent infections, anemia, thrombocytopenia and neutropenia, whereas the central nervous system (CNS) may be affected in more advanced stages of the disease with headaches, vomiting and lethargy. Pleural effusions produced by a mediastinal mass is not uncommon, which is why imaging studies such as computed tomography (CT) may be useful. The mainstay of diagnosis, however, is biopsy and flow cytometry to determine the immunophenotype of the tumor. The role of aggressive high-dose chemotherapy in modern treatment has substantially increased the rate of cure among patients, reaching 75% in children and 50% in adults [4]. Methotrexate is the single most important chemotherapeutic agent used in patients with T-ALL, either orally or intravenously [7]., while recent studies have suggested novel drugs for A-TLL patients. γ-secretase inhibitors (GSIs) that act against NOTCH receptor antagonists and nelarabine, a T-cell cytotoxic drug have been developed in recent years [4] [8]. Despite these measures, however, many patients relapse and have a poor prognosis under such circumstances [9]. Overall survival rates are much better if the tumor is diagnosed in children (up to 80%) compared to adults, in whom 5-year survival is only 45% [10] [11]. These findings indicate a detrimental need for an early diagnosis for timely initiation of therapy, so that maximal survival is achieved.

T-cell acute lymphoblastic leukemia (T-ALL) is one of the subtypes of acute lymphoblastic leukemia (ALL), the most common pediatric cancer. T-ALL comprises about 15% of all ALL cases, but it may be seen in adults as well and the cause stems from numerous genetic mutations. Namely, genes that are responsible for regulation of cell cycle, programmed cell death (known as apoptosis) and proliferation of blood cells, specifically T lymphocytes (which carry out numerous important functions in the immune system) undergo various mutations. As a result, the function of the bone marrow and production of white blood cells is altered, manifesting as the presence of recurrent infections that may be life-threatening, as well as fever. Additionally, the effects of reduced red blood cell count (anemia) and thrombocytes (thrombocytopenia) present with fatigue, easy bruising and bleeding. If the tumor has spread to the central nervous system, which is characteristic for more advanced stages of the disease, headaches, lethargy, vomiting and neck stiffness may be observed. To make the diagnosis, it is essential to obtain basic laboratory values - a complete blood count (CBC), perform a detailed physical examination and obtain a detailed patient history regarding the onset of symptoms. Imaging studies such as computed tomography (CT scan) and magnetic resonance imaging (MRI) may be useful in assessing the state of thoracic and abdominal organs, but to make a definite diagnosis, biopsy of the bone marrow and subsequent examination of the obtained sample is necessary. The focus of treatment is administration of high-dose chemotherapy consisting primarily of methotrexate and early treatment may have curative effects in the vast majority of patients. However, T-ALL is an aggressive form of malignancy and relapses are quite frequent, despite adequate therapy. It is important to point out that the prognosis is much better in children than in adults and in males compared to females, for still unknown reasons. It is estimated that almost 20% of children will die from this disease in long-term follow-up, whereas 5-year survival rates are below 50% for adults. New therapeutic strategies are being developed that target the tumor on a molecular basis, but until their use becomes solidified in general practice, this tumor poses a significant and life-threatening risk for patients.

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