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*It is thought that most translocations occur before birth during fetal development | *It is thought that most translocations occur before birth during fetal development | ||
*These translocations may trigger [[oncogene]]s to "turn on", causing unregulated [[mitosis]] where cells divide too quickly and abnormally, resulting in leukemia. | *These translocations may trigger [[oncogene]]s to "turn on", causing unregulated [[mitosis]] where cells divide too quickly and abnormally, resulting in leukemia. | ||
*It has been known that acute lymphoblastic | *It has been known that acute lymphoblastic leukemia is denoted by gross numerical and structural chromosomal abnormalities, including: | ||
**hyperdiploidy (>50 chromosomes) | |||
**hypodiploidy (<44 chromosomes) | |||
**translocations t{[12;21], [1;19], [9;22], [4;11]} | |||
**rearrangements (MYC, MLL) | |||
*However, several observations indicate that these lesions listed above alone are insufficient to induce leukemia and cooperating lesions are required | |||
*As an example, rearrangements such as t(12;21), ETV6-RUNX1, comprising 22% of pediatric ALL, are present years before the development of leukemia | |||
*Many of the genes involved encode proteins with key roles in lymphoid development | |||
*It is suggested that the initial event confers self-renewal coupled with mutation, leading to developmental arrest and a secondary cooperative event in cell cycle regulation, tumor suppression and chromatin modification, eventually leading to establishment of the leukemic clone | |||
*According with the [[World Health Organization]] (WHO) classification of acute lymphoblastic leukemia, B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities include: | *According with the [[World Health Organization]] (WHO) classification of acute lymphoblastic leukemia, B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities include: | ||
Revision as of 15:46, 15 January 2019
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Acute lymphoblastic leukemia Microchapters |
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Differentiating Acute lymphoblastic leukemia from other Diseases |
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Risk calculators and risk factors for Acute lymphoblastic leukemia pathophysiology |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]Shivali Marketkar, M.B.B.S. [3] Carlos A Lopez, M.D. [4]
Overview
Acute lymphoid leukemia arises from lymphoblasts, which are hematologic white cells that are normally involved in the hematopoiesis. Chromosomal translocations involved in the pathogenesis of acute lymphoid leukemia include translocations between the chromosomes 9 and 22, t(9;22) (q34;q11.2) BCR-ABL1, translocations between the chromosomes 12 and 21, t(12;21)(p13;q22) TEL-AML1, translocations between the chromosomes 5 and 14, t(5;14)(q31;q32)IL3-IGH and translocations between chromosomes 1 and 19 t(1;19)(q23;p13.3) TCF3-PBX1.
Pathophysiology
Physiology
The normal physiology of lymphoblast formation can be understood as follows:[1]
- Lymphoid cells are formed from pluripotent hematopoietic stem cells in the bone marrow, through a maturation process
- In the development of B cells, which includes development initiated at the level of the following cells:
- Lymphoid-primed multipotent progenitors
- Common lymphoid progenitors
- Pro–B cells
- Pre–B cells
- Mature B cells
- This maturation process is strictly regulated by the hierarchical activation of transcription factors and selection through functional signal transduction
- A lymphoblast is a altered naive lymphocyte with recasted cell morphology
- This happens when the lymphocyte is triggered by an antigen (from antigen-presenting cells) and enlarged in volume by nucleus and cytoplasmic growth as well as new mRNA and protein synthesis
- The lymphoblast then starts multiplying two to four times every 24-hours for 3-5 days, with a single lymphoblast producing approximately 1000 clones of its original naive lymphocyte, with each embodying the originally unique antigen specificity
- Finally the dividing cells transforms into effector cells, known as Plasma Cells (for B cells), Cytotoxic T cells, and Helper T cells.
Pathogenesis
- The cause of most acute lymphoblastic leukemia is not known
- In general, cancer is caused by damage to DNA that leads to uncontrolled cellular growth and spread throughout the body, either by increasing chemical signals that cause growth or interrupting chemical signals that control growth
- This damage may be caused by environmental factors such as:[2]
- chemicals
- drugs
- radiation
- In leukemias including acute lymphoblastic leukemia, chromosomal translocation occur regularly
- It is thought that most translocations occur before birth during fetal development
- These translocations may trigger oncogenes to "turn on", causing unregulated mitosis where cells divide too quickly and abnormally, resulting in leukemia.
- It has been known that acute lymphoblastic leukemia is denoted by gross numerical and structural chromosomal abnormalities, including:
- hyperdiploidy (>50 chromosomes)
- hypodiploidy (<44 chromosomes)
- translocations t{[12;21], [1;19], [9;22], [4;11]}
- rearrangements (MYC, MLL)
- However, several observations indicate that these lesions listed above alone are insufficient to induce leukemia and cooperating lesions are required
- As an example, rearrangements such as t(12;21), ETV6-RUNX1, comprising 22% of pediatric ALL, are present years before the development of leukemia
- Many of the genes involved encode proteins with key roles in lymphoid development
- It is suggested that the initial event confers self-renewal coupled with mutation, leading to developmental arrest and a secondary cooperative event in cell cycle regulation, tumor suppression and chromatin modification, eventually leading to establishment of the leukemic clone
- According with the World Health Organization (WHO) classification of acute lymphoblastic leukemia, B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities include:
- B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2), BCR-ABL1
- B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged
- B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22) TEL-AML1 (ETV6-RUNX1)
- B lymphoblastic leukemia/lymphoma with hyperdiploidy
- B lymphoblastic leukemia/lymphoma with hypodiploidy
- B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32) IL3-IGH
- B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3) TCF3-PBX1
- According with the French-American-British (FAB) classification of acute lymphoblastic leukemia is divided into 3 subtypes:
- ALL-L1: small uniform cells
- ALL-L2: large varied cells
- ALL-L3: large varied cells with vacuoles (bubble-like features)
- Malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow
- Acute lymphoblastic leukemia causes damage and death by crowding out normal cells in the bone marrow, and by spreading (metastasizing) to other organs
Markers
B-cell acute lymphoblastic leukemia:[3]
T-cell acute lymphoblastic leukemia:
Genetics
- Cytogenetics, the study of characteristic large changes in the chromosomes of cancer cells, has been increasingly recognized as an important predictor of outcome in acute lymphoblastic leukemia.[4]
- It has been recognized for many years that some patients presenting with acute leukemia may have a cytogenetic abnormality that is cytogenetically indistinguishable from the Philadelphia chromosome (Ph1) This occurs in about 20% of adults and a small percentage of children with acute Lymphoblastic leukemia
- The advances in the conventional cytogenetic techniques, as the fluorescence in situ hybridization, have displayed the chromosomal rearrangements[5]
- In has been documented that the incidence of chromosomal change is related with the age
- The translocation t(9;22)(q34;q11) increases with the passage of each consecutive decade, up to 24% between the 40-to 49 years old[5]
- The t(4;11) (q21;q23) and t(1;19) (q23;q13) are seldomly seen in patients older than 60 years old
- The t (8;14) (q24;q32) and t(14;18)(q32;q21) translocation rates increase with age
- The hiperdipoidia is seen in 13% of patients under 20 years old and only 5% of elderly patients
- The hypodiploidy and complex karyotype (presence of more than 2 chromosomal abnormalities) also increase with age of 4% in the range of 15 to 19 years old to 16% older than 60 years old
| Cytogenetic change | Risk category |
|---|---|
| Philadelphia chromosome | Poor prognosis |
| t(4;11)(q21;q23) | Poor prognosis |
| t(8;14)(q24.1;q32) | Poor prognosis |
| Complex karyotype (more than four abnormalities) | Poor prognosis |
| Low hypodiploidy or near triploidy | Poor prognosis |
| High hypodiploidy | Good prognosis |
| del(9p) | Good prognosis |
Gallery
References
- ↑ Zuckerman T, Rowe JM (2014). "Pathogenesis and prognostication in acute lymphoblastic leukemia". F1000Prime Rep. 6: 59. doi:10.12703/P6-59. PMC 4108947. PMID 25184049.
- ↑ Inaba H, Greaves M, Mullighan CG (June 2013). "Acute lymphoblastic leukaemia". Lancet. 381 (9881): 1943–55. doi:10.1016/S0140-6736(12)62187-4. PMC 3816716. PMID 23523389.
- ↑ "National Cancer Institute".
- ↑ Moorman A, Harrison C, Buck G, Richards S, Secker-Walker L, Martineau M, Vance G, Cherry A, Higgins R, Fielding A, Foroni L, Paietta E, Tallman M, Litzow M, Wiernik P, Rowe J, Goldstone A, Dewald G (2007). "Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial". Blood. 109 (8): 3189–97. PMID 17170120.
- ↑ 5.0 5.1 P., M.; Borjas-Gutierrez, C.; M., G.; E., L.; M., A.; R., J. (2013). "Pathophysiology of Acute Lymphoblastic Leukemia". doi:10.5772/54652.