This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.
What is T-ALL?
Acute T-cell lymphoblastic leukemia (T-ALL), as its name suggests, is an acute form of blood cancer affecting T-cells (a type of white blood cell that is categorized as lymphocyte; see about.com for more information), and is characterized by accumulation of immature T-cells [1]. The word “acute” indicates that the disease progresses very quickly and, if no treatment is given, T-ALL patients may die in weeks (http://communications.med.nyu.edu). "Lymphoblastic" describes the type of leukemic cell that contribute to the cancer, namely lymphoblasts, or more specifically T-lymphoblasts. The video below provides an overview of acute lymphoblastic leukemia (ALL).
From YouTube, 2011. Acute lymphoblastic leukemia in children. Retrieved from
http://www.youtube.com/watch?v=17OwUs9ACWo&feature=results_video&playnext=1&list=PL554B00D52C5F3C3C.
http://www.youtube.com/watch?v=17OwUs9ACWo&feature=results_video&playnext=1&list=PL554B00D52C5F3C3C.
Symptoms
Pathology of the disease arises from the accumulation of immature T-cells, which interferes with production of healthy blood cells in bone marrow and organs such as spleen and thymus (www.patient.co.uk and www.cancer.org). Consequently, there is insufficient number of healthy blood cells in T-ALL patients, giving rise to the symptoms of T-ALL (Table 1).
Table 1: Symptoms of T-ALL (Information adapted from www.cancer.org.)
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_ In addition, the accumulation of immature T-cells often leads to the swelling of certain organs, resulting in symptoms associated with organomegaly (enlargement of organs) (Figure 1). Another high-risk complication that is often associated with T-ALL is the spread of leukemic cells to the central nervous system (CNS) (ecancernews). Hence, treatment to reduce this risk is usually given along with the treatment of T-ALL itself.
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Figure
1: Symptoms of T-ALL. (Figure from MedlinePlus,
modified with information from www.cancer.org)
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Prevalence
In general, ALL is predominantly found in children (Figure 2; Figure 3) and people over 70 years old [2]. It is the leading form of cancer in children between 1 to 7 years old and the most prevalent form of leukemia in people below 20 years of age (www.lls.org). Among all the ALL cases in children, 15% is contributed by T-ALL, whereas in the adult ALL population, T-ALL accounts for 25% of ALL cases (Figure 3) [3]. In terms of geographical distribution, T-ALL is particularly prevalent in Southern India, with 43.1% of its population affected with the disease [4]. In comparison, Western countries have a much lower incidence of T-ALL, ranging from 15 to 25% of the population [4]. It has also been observed that T-ALL incidence in males is higher compared to females [5]. Research has identified X-linked gene associated with T-ALL [5], although it remains controversial whether or not this account for the higher incidence in males [6].
In general, ALL is predominantly found in children (Figure 2; Figure 3) and people over 70 years old [2]. It is the leading form of cancer in children between 1 to 7 years old and the most prevalent form of leukemia in people below 20 years of age (www.lls.org). Among all the ALL cases in children, 15% is contributed by T-ALL, whereas in the adult ALL population, T-ALL accounts for 25% of ALL cases (Figure 3) [3]. In terms of geographical distribution, T-ALL is particularly prevalent in Southern India, with 43.1% of its population affected with the disease [4]. In comparison, Western countries have a much lower incidence of T-ALL, ranging from 15 to 25% of the population [4]. It has also been observed that T-ALL incidence in males is higher compared to females [5]. Research has identified X-linked gene associated with T-ALL [5], although it remains controversial whether or not this account for the higher incidence in males [6].
Figure 2: Prevalence of T-ALL in children (Information obtained from atlasgeneticsoncology.org)
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Figure 3: Distribution of ALL (Information obtained from Chiaretti, S., & Foa, R., 2009. doi: 10.3324/haematol.2008.004150)
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T-ALL and NOTCH1
In T-ALL, the failure of T-lymphoblasts to develop into mature T-cells is associated with genetic abnormalities [3]. However, no single gene can be isolated as the sole factor that leads to the disease. In other words, it is likely that the disease is caused by the cumulative effects of multiple genetic lesions. Nevertheless, genetic mutations involving certain genes appear to be more common than others in patients with T-ALL, and the NOTCH1 gene is one of them. Mutations in NOTCH1 that cause aberrant activation of the Notch signaling pathway have been identified in over 50% of T-ALL cases [3][7].
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Figure 4: NOTCH1 gene (yellow arrow) is on chromosome 9. (Figure from Genetics Home Reference)
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Diagnosis and treatment
In order to confirm whether a patient indeed has T-ALL, the diagnosis tests presented in Figure 5 are usually performed. Results from these tests also facilitate selection of appropriate therapies [2].
In terms of treatment, the most common treatment for T-ALL patients is chemotherapy, although some patients may also be advised to undergo bone marrow transplantation (marrow.org). Chemotherapy is aimed at killing off the cancerous cells and allowing normal blood cells to be produced (mayoclinic). There are 3 phases of chemotherapy in the treatment of T-ALL. The first and second phases are induction chemotherapy and consolidation therapy respectively. Both are of higher intensity (referring to chemotherapy dose) compared to the third phase, which is the maintenance therapy (Table 2) (marrow.org). |
Figure 5: Diagnosis process for T-ALL (Information obtained from: www.cap.org)
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Table 2: Chemotherapy treatment phases. (Information derived from marrow.org)
According to marrow.org, not all patients undergo all 3 phases of the treatment. After phase 1 treatment, some patients may be advised to undergo bone marrow transplantation, especially those with increased risk of cancer recurrence. However, due to the risk of deleterious side effects of the bone marrow transplantation, it is not used in the treatment of all T-ALL cases. Among the side-effects are rejection by immune system and viral/bacterial/fungal infection (www.stjude.org). For general information about bone marrow transplantation, watch the video on the right. Apart from these treatments, there is often the need to eliminate cancer cells that might have spread to the central nervous system (CNS) because ALL patients have a high risk of developing CNS leukemia (www.cancer.gov - child ALL; adult ALL). Thus, CNS prophylaxis (such as intrathecal chemotherapy and cranial radiation) is usually administered along with the aforementioned chemotherapy (www.cancer.gov). |
From YouTube, 2009. Bone Marrow Transplant-Mayo Clinic. Retrieved from http://www.youtube.com/watch?v=GIy2nMnuGGI&feature=related.
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Prognosis
In the past, T-ALL had a more pessimistic prognosis compared to B-ALL [2][8], but there have been improvements on the treatments for T-ALL in recent years (atlasgeneticsoncology.org). In a report published in 2002, the overall complete remission rate for T-ALL was 85% and the long-term leukemia free survival rate is 46% [9]. Distinguishing between children and adult population, two reports (published in 2004 and 2007 respectively) revealed that the 5-year event free survival rate for T-ALL children after treatment was as high as 80% (atlasgeneticoncology.org)[10], whereas the average survival rate for adults was 40% (marrow.org).
In the past, T-ALL had a more pessimistic prognosis compared to B-ALL [2][8], but there have been improvements on the treatments for T-ALL in recent years (atlasgeneticsoncology.org). In a report published in 2002, the overall complete remission rate for T-ALL was 85% and the long-term leukemia free survival rate is 46% [9]. Distinguishing between children and adult population, two reports (published in 2004 and 2007 respectively) revealed that the 5-year event free survival rate for T-ALL children after treatment was as high as 80% (atlasgeneticoncology.org)[10], whereas the average survival rate for adults was 40% (marrow.org).
References:
1. Demarest, R.M., Dahmane, N., & Caoibianco, A.J. (2011). Notch is oncogenic dominant in T-cell acute lymphoblastic leukemia. Blood 117(10): 2901-2909. doi: 10.1182/blood-2010-05-286351
2. College of American Pathologists. (n.d.). Electronic references. Retrieved February 1, 2012, from http://www.cap.org/apps/docs/reference/myBiopsy/acute_lymphocytic_leukemia.html.
3. Chiaretti, S., & Foa, R. (2009). T-cell acute lymphoblastic leukemia. Haematologica 94(2), 160. doi: 10.3324/haematol.2008.004150
4. Sudhakar, N., Nirmala, K., Rajalekshmy, K.R., & Rajkumar, T. (2008). Does TAL-1 Deletion Contribute to the High Incidence of T-cell Acute Lymphoblastic Leukemia in South Indian? Asian Pacific Journal of Cancer Prevention, 9: 127-130. [PubMed]
5. Vlierberghe, P.V. et al. (2010). PHF6 mutations in T-cell acute lymphoblastic leukemia. Nature genetics 42(4): 338-342. doi: 10.1038/ng.542
6. Wang, Q. et al. (2011). Mutations of PHF6 are associated with mutations of NOTCH1, JAK1 and rearrangement of SET-NUP214 in T-cell acute lymphoblastic leukemia. Haematologica 96(12): 1808-1814. doi: 10.3324/haematol.2011.043083
7. Weng, A.P., Ferrando, A.A., Lee, W., Morris IV, J.P., Silverman, L.B., Sanchez-Irizarry, C., Blacklow, S.C., Look, A.T., & Aster, J.C. (2004). Activating Mutations of NOTCH1 in Human T cell Acute Lymphoblastic Leukemia. Science 306 (5694) :269-271. doi: 10.1126/science.1102160
8. Dermarest, R.M., Ratti, F., & Capobianco, A.J. (2008). It's All About Notch. Oncogene, 27(38), 5082. doi: 10.1038/onc.2008.222
9. Gokbuget, N., & Hoelzer, D. (2002). Recent approaches in acute lymphoblastic leukemia in adults. Reviews in clinical & environmental hematology, 6(2): 114-141. [PubMed]
10. Pui, C.H., Relling, M.V., & Downing, J.R. (2004). Mechanisms of disease: Acute lymphoblastic leukemia. The New England Journal of Medicine. 350(15): 1535-1548. Retrieved from: http://www.nejm.org/doi/full/10.1056/NEJMra023001
1. Demarest, R.M., Dahmane, N., & Caoibianco, A.J. (2011). Notch is oncogenic dominant in T-cell acute lymphoblastic leukemia. Blood 117(10): 2901-2909. doi: 10.1182/blood-2010-05-286351
2. College of American Pathologists. (n.d.). Electronic references. Retrieved February 1, 2012, from http://www.cap.org/apps/docs/reference/myBiopsy/acute_lymphocytic_leukemia.html.
3. Chiaretti, S., & Foa, R. (2009). T-cell acute lymphoblastic leukemia. Haematologica 94(2), 160. doi: 10.3324/haematol.2008.004150
4. Sudhakar, N., Nirmala, K., Rajalekshmy, K.R., & Rajkumar, T. (2008). Does TAL-1 Deletion Contribute to the High Incidence of T-cell Acute Lymphoblastic Leukemia in South Indian? Asian Pacific Journal of Cancer Prevention, 9: 127-130. [PubMed]
5. Vlierberghe, P.V. et al. (2010). PHF6 mutations in T-cell acute lymphoblastic leukemia. Nature genetics 42(4): 338-342. doi: 10.1038/ng.542
6. Wang, Q. et al. (2011). Mutations of PHF6 are associated with mutations of NOTCH1, JAK1 and rearrangement of SET-NUP214 in T-cell acute lymphoblastic leukemia. Haematologica 96(12): 1808-1814. doi: 10.3324/haematol.2011.043083
7. Weng, A.P., Ferrando, A.A., Lee, W., Morris IV, J.P., Silverman, L.B., Sanchez-Irizarry, C., Blacklow, S.C., Look, A.T., & Aster, J.C. (2004). Activating Mutations of NOTCH1 in Human T cell Acute Lymphoblastic Leukemia. Science 306 (5694) :269-271. doi: 10.1126/science.1102160
8. Dermarest, R.M., Ratti, F., & Capobianco, A.J. (2008). It's All About Notch. Oncogene, 27(38), 5082. doi: 10.1038/onc.2008.222
9. Gokbuget, N., & Hoelzer, D. (2002). Recent approaches in acute lymphoblastic leukemia in adults. Reviews in clinical & environmental hematology, 6(2): 114-141. [PubMed]
10. Pui, C.H., Relling, M.V., & Downing, J.R. (2004). Mechanisms of disease: Acute lymphoblastic leukemia. The New England Journal of Medicine. 350(15): 1535-1548. Retrieved from: http://www.nejm.org/doi/full/10.1056/NEJMra023001
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