Acute lymphoblastic leukemia pathophysiology

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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[2]
  • In the development of B cells, which includes development initiated at the level of the following cells:[3]
    • Lymphoid-primed multipotent progenitors[4]
    • Common lymphoid progenitors[5]
    • Pro–B cells[6]
    • Pre–B cells[7]
    • Mature B cells[8]
  • This maturation process is strictly regulated by the hierarchical activation of transcription factors and selection through functional signal transduction[9]
  • A lymphoblast is a altered naive lymphocyte with recasted cell morphology[10]
  • 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[11]
  • 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[12]
  • Finally the dividing cells transforms into effector cells, known as Plasma Cells (for B cells), Cytotoxic T cells, and Helper T cells[13]

Pathogenesis

  • The cause of most acute lymphoblastic leukemia is not known[14]
  • 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:[15]
    • 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 defects, including:
    • Hyperdiploidy (>50 chromosomes)
    • Hypodiploidy (<44 chromosomes)
    • Translocations t{[12;21], [1;19], [9;22], [4;11]}
    • Rearrangements (MYC, MLL)
  • However, several studies have shown that these lesions listed above alone are not enough to cause leukemia and cooperating lesions have to be involved
  • For example, mutations such as t(12;21), ETV6-RUNX1, comprising 22% of pediatric ALL, are present years before the development of leukemia
  • Many of these genes are encoding proteins with key roles in lymphoid development
  • It is advised that the initial event conveys self-renewal coupled with mutation, going into developmental arrest and a secondary cooperative event in cell cycle regulation, tumor suppression and chromatin modification, eventually leading to formation of the leukemic clone
  • Acute lymphoblastic leukemia genomes typically have less structural genetic changes than many solid tumors
  • More than 50 recurring regions of DNA copy number changes have been discovered
  • They are commonly focal deletions, limited to one or few genes that take part in normal lymphoid development:
  • T-lineage acute lymphoblastic leukemia is understood as activated mutations of NOTCH1 and rearrangements of transcription factors which are the follwoing
  • Arrangements of the full range of acute lymphoblastic luekemia subtypes has shown that the alteration of multiple cellular pathways, which includes the following:
  • The disruption of these pathways listed above are typical events in different acute lymphoblastic leukemia subtypes.

BCR-ABL1-like B-ALL and IKZF1 transformation

  • BCR-ABL1-like acute lymphoblastic leukemia has the gene expression signature similar to that of BCR-ABL1 acute lymphoblastic leukemia, while not having the BCR-ABL1 translocation
  • More than 80% of patients with BCR-ABL1-like acute lymphoblastic leukemia have defects in genes that have to do with B-cell development, such as:
  • The prevalence of BCR-ABL1-like acute lymphoblastic leukemia is almost 15% in pediatric B-cell acute lymphoblastic leukemia's and it known to be associated with an inferior survival rate (5-year event-free-survival <60%), as is BCR-ABL1 acute lymphoblastic leukemia

CRLF2 over expression and JAK mutations

  • Up to half of BCR-ABL1-like cases contain rearrangement of CRLF2 causing an over-expression of CRLF2 on the surface of lymphoblasts that may be picked up by immunophenotyping
  • Additionally, almost half of CRLF2-rearranged cases have concomitant initiating mutations of the JAK genes JAK1 and JAK2
  • The JAK/signal transducers and initiators of transcription (STAT) pathway controls signaling of the following:
    • Cytokine
    • Chemokine
    • Growth factor receptors
  • Signaling is done via the JAK non-receptor tyrosine kinases and the STAT family of transcription factors
  • These changes cause an activation of JAK-STAT signaling that may be responsive to therapy with JAK inhibitors such as ruxolitinib, and this is being explored at the moment as a therapeutic strategy
  • Ongoing next-generation sequencing studies in childhood and adult acute lymphoblastic leukemia are made to define the variety of kinase-activating changes in BCR-ABL1-like acute lymphoblastic leukemia and to develop clinical trials with a goal of leading patients with BCR-ABL1-like acute lymphoblastic leukemia to appropriate tyrosine-kinase inhibitor (TKI) therapy .

Hypodiploid acute lymphoblastic leukemia

Two subtypes of hypodiploid acute lymphoblastic leukemia have been documented according to the intensity of aneuploidy:

  • Near-haploid cases with 24 to 31 chromosomes
  • Low-hypodiploid cases with 32 to 39 chromosomes
  • There has been an analysis recently done of a large cohort of more than 120 hypodiploid pediatric acute lymphoblastic leukemia patients has shown that near-haploid and low-hypodiploid acute lymphoblastic leukemia have different transcriptomic signatures and submicroscopic genetic alterations
  • A large number of near-haploid cases have alteration targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (13%)
  • In comparison, low-hypodiploid acute lymphoblastic leukemias with 32–39 chromosomes are noted to have changes in the following
    • TP53 (91.2%)
    • IKZF2 (53%)
    • RB1 (41%)
  • Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are responsive to PI3K inhibitors, showing that these drugs might be used for this aggressive form of leukemia

T cell acute lymphoblastic leukemia

  • T-lineage acute lymphoblastic leukemia is has been known to have an older age of onset, male sex predominance, and poor outcome in comparison with b cell acute lymphoblastic leukemia
  • As of recent the next-generation sequencing identified sequence mutations and, less common deletion of PHF6 in 16% and 38% of childhood and adult t cell acute lymphoblastic leukemia cases, respectively
  • The role of PHF6 in leukemogenesis is not fully understood, but the loss-of-function alterations have shown that PHF6 is a tumor suppressor
  • Early T-cell precursor of acute lymphoblastic luekemia is an aggressive subtype of immature leukemia that is known for a high proportion of t cell acute lymphoblastic leukemia treatment failures
  • Recent studies found this type of leukemia to be associated with loss-of-function mutations in the following:
    • Hematopoietic regulators (GATA3, IKZF1, RUNX1, ETV6)
    • Gain-of-function mutations in Ras, FLT3, JAK, and IL7R,
    • Inactivating mutations in epigenetic regulators (EZH2, SUZ12, EED, SETD2, DNMT3A)
  • The mutational spectrum of this acute lymphoblastic leukemia subtype is similar to that observed in myeloid leukemias
  • Comparison of its transcriptional profile with those of normal human hematopoietic progenitors showed a great similarity to hematopoietic stem and early myeloid progenitors
  • Thus, the T-cell precursor acute lymphoblastic leukemia is likely to show a part of a spectrum of immature, stem cell-like leukemias
  • Epigenetic modifiers and agents targeting JAK-STAT signaling are currently being investigated

WHO and FAB classification

  • 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
  • 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:[16]

  • Typically express CD10, CD19, and CD34 on their surface along, with nuclear terminal deoxynucleotide transferase (TdT)

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.[17]
  • 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[18]
  • 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[18]
  • 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 Target gene Frequency in childhood in % Frequency in adulthood in % Risk category
Philadelphia chromosome BCR-ABL1 3 to 5 25 to 30 Poor prognosis
t(4;11)(q21;q23) MLL-AF4 2 to 3 3 to 7 Poor prognosis
t(8;14)(q24.1;q32) Non-TCR(NOTCH,HOX11,JAK1) 60 Favorable prognosis
Complex karyotype (more than four abnormalities) Poor prognosis
hypodiploidy or near triploidy 5 to 6 3 Poor prognosis
High hyperdiploidy 20 to 30 7 Good prognosis
T cell acute lymphoblastic leukemia TCR

References

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  2. Weiskopf K, Schnorr PJ, Pang WW, Chao MP, Chhabra A, Seita J; et al. (2016). "Myeloid Cell Origins, Differentiation, and Clinical Implications". Microbiol Spectr. 4 (5). doi:10.1128/microbiolspec.MCHD-0031-2016. PMC 5119546. PMID 27763252.
  3. Hoffman W, Lakkis FG, Chalasani G (2016). "B Cells, Antibodies, and More". Clin J Am Soc Nephrol. 11 (1): 137–54. doi:10.2215/CJN.09430915. PMC 4702236. PMID 26700440.
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  5. Mansson, R.; Zandi, S.; Welinder, E.; Tsapogas, P.; Sakaguchi, N.; Bryder, D.; Sigvardsson, M. (2009). "Single-cell analysis of the common lymphoid progenitor compartment reveals functional and molecular heterogeneity". Blood. 115 (13): 2601–2609. doi:10.1182/blood-2009-08-236398. ISSN 0006-4971.
  6. Bertrand, F. E. (2001). "Pro-B-cell to pre-B-cell development in B-lineage acute lymphoblastic leukemia expressing the MLL/AF4 fusion protein". Blood. 98 (12): 3398–3405. doi:10.1182/blood.V98.12.3398. ISSN 0006-4971.
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  11. Saitakis, Michael; Dogniaux, Stéphanie; Goudot, Christel; Bufi, Nathalie; Asnacios, Sophie; Maurin, Mathieu; Randriamampita, Clotilde; Asnacios, Atef; Hivroz, Claire (2017). "Different TCR-induced T lymphocyte responses are potentiated by stiffness with variable sensitivity". eLife. 6. doi:10.7554/eLife.23190. ISSN 2050-084X.
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