Etiology
The cause of acute lymphoblastic leukemia (ALL) is unknown. Certain factors have been associated with the development of ALL.
Genetic
The diagnosis of ALL in a monozygotic twin (at <6 years of age) is associated with a 10% to 15% likelihood that the second twin will develop ALL.[11]
ALL is associated with trisomy 21, Klinefelter syndrome, and inherited diseases with excessive chromosomal fragility such as Fanconi anemia, Bloom syndrome, and ataxia-telangiectasia.[1][2][11][12][13]
There is growing evidence suggesting a germline predisposition to ALL.[14][15][16][17][18] Germline mutations linked to ALL are reported in approximately 4% of children with ALL.[14]
Environmental: including radiation exposure and smoking.[1][3][19]
Treatment with chemotherapy.[19]
Folate metabolism polymorphisms have been associated with risk for ALL in case-control studies.[24][25][26][27]
Pathophysiology
In ALL, genetic abnormalities of a lymphoid progenitor cell results in uncontrolled proliferation and clonal expansion. The leukemic lymphoblasts infiltrate the bone marrow and other organs, which disrupts their normal function. Leukemic lymphoblasts may also circulate in the blood.
The leukemic lymphoblasts represent a clonal expansion of a single cell.[2][28][29][30]
The leukemic lymphoblasts duplicate most of the features of the lymphoid progenitor cell. Genetic abnormalities in ALL include chromosomal rearrangements (e.g., translocations), aneuploidy (abnormal number of chromosomes), and other genetic mutations. Chromosomal translocations or aneuploidy are found in 75% of cases. Translocations are commonly recurring and rarely are classified as random translocations.[29][30][31][32]
Philadelphia chromosome-positive B-ALL (Ph+ B-ALL)
One of the most common and clinically important chromosomal translocations in adult B-ALL is t(9;22)(q34;q11), which results in the BCR::ABL1 fusion gene on chromosome 22 (i.e., the Philadelphia chromosome).[33] The BCR::ABL1 fusion gene encodes an active tyrosine kinase that transforms normal hematopoietic stem cells into malignant cells. [Figure caption and citation for the preceding image starts]: BCR::ABL1 translocationFrom the collection of Dr Han Myint and Dr Robert Chen; used with permission [Citation ends].
Philadelphia-like B-ALL (Ph-like B-ALL)
Ph-like B-ALL is a high-risk subtype that has a similar gene expression profile to Ph+ B-ALL, but lacks the BCR::ABL1 fusion gene (Philadelphia chromosome).[33] Ph-like B-ALL comprises 10% and 13% of standard- and high-risk childhood B-ALL cases, respectively.[29]
The frequency of Ph-like B-ALL increases with age, accounting for >25% of young adult cases.[33] Presence of Ph-like B-ALL is associated with an unfavorable outcome.[34][35]
Patients with Ph-like B-ALL can be categorized as follows:[36]
Type I, ABL-class fusions (ABL1, ABL2, CSF1R, PDGFRB)
Type II, erythropoietin-receptor (EPOR) or JAK2 rearrangements
Type III, cytokine receptor-like factor 2 (CRLF2) rearrangements (often accompanied by JAK2 mutations and JAK-STAT signal activation)
Type IV, other mutations activating JAK-STAT signaling (IL7R, FLT3, SH2B3, TYK2, IL2RB)
Type V, uncommon miscellaneous kinase mutations (NTRK3, DGKH)
Type VI, RAS-pathway mutations (KRAS, NRAS, PTPN11, NF1)
Type VII, no mutations in kinase genes.
Other genetic abnormalities
FLT3 and NOTCH1 have been identified as genes mutated in mixed-lineage leukemia (MLL)/hyperdiploid and T-ALL, respectively.[37] CREBBP mutations are seen in 18% of relapsed ALL and may confer resistance to therapy.[38] PAX5 gene is mutated in up to 30% of pediatric patients with ALL.[39][40] PHF6 mutations are seen in 38% of adult T-ALL samples.[41] CDKN2A mutations are seen in 42% of cases of T-ALL.[42]
Some gene rearrangements may result in loss or gain of function mutations involving transcription factors that play a role in hematopoietic development. An example of such gene rearrangement is the t(12;21)(p13;q22) chromosomal translocation that results in the fusion gene ETV6::RUNX1 (also known as TEL::AML1).[1][3]
Loss or inactivation of tumor-suppressor genes via deletions and gene rearrangements (e.g., IKZF1, p16INK4) is associated with development of ALL.[43][44] IKZF1 mutations may be a predictor of relapse.[45] Deletion of IKZF1 with co-occurring deletions in CDKN2A, CDKN2B, PAX5, or PAR1 (in the absence of ERG deletion) defines a subgroup referred to as "IKZF1 plus", which is associated with a particularly poor prognosis.[46]
Some recurrent genetic abnormalities (e.g., BCR::ABL1, KMT2A rearrangement, ETV6::RUNX1) have been incorporated into disease classification systems from the World Health Organization (WHO) and International Consensus Classification (ICC) to subclassify ALL.[6][7] See Classification.
Classification
The 5th edition of the World Health Organization classification of haematolymphoid tumours: lymphoid neoplasms[6]
The classification of ALL (and entities) is based on lineage (B-ALL or T-ALL) and the presence of cytogenetic/molecular abnormalities.
B-cell lymphoblastic leukemias/lymphomas:
B-lymphoblastic leukemia/lymphoma, not otherwise specified
B-lymphoblastic leukemia/lymphoma with high hyperdiploidy
B-lymphoblastic leukemia/lymphoma with hypodiploidy
B-lymphoblastic leukemia/lymphoma with iAMP21
B-lymphoblastic leukemia/lymphoma with BCR::ABL1 fusion
B-lymphoblastic leukemia/lymphoma with BCR::ABL1-like features
B-lymphoblastic leukemia/lymphoma with KMT2A rearrangement
B-lymphoblastic leukemia/lymphoma with ETV6::RUNX1 fusion
B-lymphoblastic leukemia/lymphoma with ETV6::RUNX1-like features
B-lymphoblastic leukemia/lymphoma with TCF3::PBX1 fusion
B-lymphoblastic leukemia/lymphoma with IGH::IL3 fusion
B-lymphoblastic leukemia/lymphoma with TCF3::HLF fusion
B-lymphoblastic leukemia/lymphoma with other defined genetic abnormalities (e.g., DUX4, MEF2D, or ZNF384 rearrangements)
T-lymphoblastic leukemia/lymphoma:
T-lymphoblastic leukemia/lymphoma, not otherwise specified
Early T-precursor lymphoblastic leukemia/lymphoma
International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias[7]
The classification of ALL (and entities) is based on lineage (B-ALL or T-ALL) and the presence of cytogenetic/molecular abnormalities.
B-cell acute lymphoblastic leukemia/lymphoma
B-ALL with recurrent genetic abnormalities
B-ALL with t(9;22)(q34.1;q11.2)/BCR::ABL1
with lymphoid only involvement
with multilineage involvement
B-ALL with t(v;11q23.3)/KMT2A rearranged
B-ALL with t(12;21)(p13.2;q22.1)/ETV6::RUNX1
B-ALL, hyperdiploid
B-ALL, low hypodiploid
B-ALL, near haploid
B-ALL with t(5;14)(q31.1;q32.3)/IL3::IGH
B-ALL with t(1;19)(q23.3;p13.3)/TCF3::PBX1
B-ALL, BCR::ABL1-like, ABL-1 class rearranged
B-ALL, BCR::ABL1-like, JAK-STAT activated
B-ALL, BCR::ABL1-like, not otherwise specified
B-ALL with iAMP21
B-ALL with MYC rearrangement
B-ALL with DUX4 rearrangement
B-ALL with MEF2D rearrangement
B-ALL with ZNF384(362) rearrangement
B-ALL with NUTM1 rearrangement
B-ALL with HLF rearrangement
B-ALL with UBTF::ATXN7L3/PAN3,CDX2 ("CDX2/UBTF")
B-ALL with mutated IKZF1 N159Y
B-ALL with mutated PAX5 P80R
B-ALL, not otherwise specified
Provisional entity: B-ALL, ETV6::RUNX1-like
Provisional entity: B-ALL, with PAX5 alteration
Provisional entity: B-ALL, with mutated ZEB2 (p.H1038R)/IGH::CEBPE
Provisional entity: B-ALL, ZNF384 rearranged-like
Provisional entity: B-ALL, KMT2A rearranged-like
T-cell acute lymphoblastic leukemia/lymphoma
Early T-cell precursor ALL with BCL11B rearrangement
Early T-cell precursor ALL, not otherwise specified
T-ALL, not otherwise specified
Provisional entity: T-ALL, HOXA dysregulated
Provisional entity: T-ALL, SPI1 rearrangement
Provisional entity: T-ALL, TLX1 rearrangement
Provisional entity: T-ALL, TLX3 rearrangement
Provisional entity: T-ALL, NKX2 rearrangement
Provisional entity: T-ALL, TAL1-2 rearrangement
Provisional entity: T-ALL, LMO1-2 rearrangement
Provisional entity: T-ALL, BHLH, other
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