Early T-Cell Precursor Lymphoblastic Leukemia
Fei Yang, MD, FACMG, Kaiser Permanente Northwest
Cancer Sub-Classification / Subtype
Early T-Cell Precursor Lymphoblastic Leukemia (ETP-ALL)
Definition / Description of Disease
Early T-Cell Precursor Lymphoblastic Leukemia (ETP-ALL) is a subtype of T-Lymphoblastic Leukemia (T-ALL) and is suggested to derive from thymic cells at the early T-cell precursor (ETP) differentiation stage. The normal counterpart is the ETP cells that are the earliest thymic progenitors immigrated from the bone marrow to the thymus, with retention of a certain level of multilineage pluripotency rather than common lymphoid progenitors . The ETP-ALL subtype has characteristic immunophenotypic and genomic profile compared with other subtypes of T-ALL. Under the 2016 version World Health Organization (WHO) classification, ETP-ALL is defined based on the immunophenotype of the leukemic cells:
- positive for intracytoplasmic CD3 and CD7, and positive (≥25% of blasts population) for at least one stem cell/myeloid marker (CD117, CD34, HLA-DR, CD13, CD33, CD11b, or CD65)
- negative to dim positive for CD5 (<75% positive)
- negative for CD1a, CD8, and MPO
However, the aforementioned immunophenotypic criteria have been reported not be able to identify all ETP-ALL cases as detected by gene expression profiling, and "negativity for CD4" has been proposed to be added to the criteria .
Synonyms / Terminology
Early thymic precursor (ETP) acute lymphoblastic leukemia (ALL)
Epidemiology / Prevalence
The clinical features of ETP-ALL are similar to that of other subtypes of T-ALL, including a high leukocyte count, anterior mediastinal mass or other tissue mass, lymphadenopathy, hepatosplenomegaly. Some patients who develop an anterior mediastinal mass can lead to superior vena cava syndrome.
Sites of Involvement
Currently there is no specific morphologic feature reported for ETP-ALL.
|Positive (universal)||intracytoplasmic CD3, CD7, and at least one stem cell or myeloid antigen (CD34, HLA-DR, CD13, CD33, CD117, CD11b, CD65)|
|Positive (subset)||dim expression of CD5 (<75% positive), CD2|
|Negative (universal)||CD1a, CD8|
Chromosomal Rearrangements (Gene Fusions)
MEF2C (5q14) rearrangement or rearrangement involving MEF2C-related cofactors have been reported in about 50% of ETP-ALL cases, which have been validated in an independent ETP-ALL patient cohort. Ectopic MEF2C expression due to rearrangement has been demonstrated as an oncogenic driver of ETP-ALL by upregulating LMO2 and LYL1, which lead to differentiation block of early thymocytes.
STIL-TAL1 fusion was only found in 3/23 ETP-ALL cases but not in 7 T-lymphoid/myeloid mixed phenotype acute leukemia (T/M-MPAL) cases in a study by Noronha et al , which could potentially help in distinguish these two disease entities. Further studies are warranted to confirm this finding.
Other chromosomal rearrangements involving KMT2A have been observed in ETP-ALL .
Individual Region Genomic Gain/Loss/LOH
Currently there is no specific copy number alterations/LOH that is associated with ETP-ALL.
Characteristic Chromosomal Patterns
Currently there is no specific chromosomal alteration that is characteristic for ETP-ALL.
Gene Mutations (SNV/INDEL)
Genes encoding transcription factors for development and differentiation (ETV6, GATA3, HOXA, LMO2, RUNX1, WT1), kinase signaling (FLT3, JAK1, JAK3, IL7R, KRAS, NRAS), and epigenetic modifiers (DNMT3A, EED, EZH2, PHF6, SUZ12) are commonly mutated in ETP-ALL . More typical T-ALL mutations, such as NOTCH1 mutations and CDKN1/2 mutations are less frequent in ETP-ALL .
|Gene; Genetic Alteration||Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)||Prevalence (COSMIC / TCGA / Other)||Concomitant Mutations||Mutually Exclusive Mutations||Diagnostic Significance (Yes, No or Unknown)||Prognostic Significance (Yes, No or Unknown)||Therapeutic Significance (Yes, No or Unknown)||Notes|
|IL7R; Variable activating mutations||Oncogene||33 - 42% in adult ETP-ALL ||core componenets of the PRC2: EZH2, SUZ12, and EED||associated with slow response to chemotherapy ||Ruxolitinib is evaluated in pre-clinical and clinical studies |
|Components of PRC2: EZH2, SUZ12, EED; variable LOF mutations||TSG||48% of pediatric ETP-ALL ||BET inhibitors are evaluated in the pre-clinical studies |
|FLT3; Activating mutations including ITD and TKD||Oncogene||35% of adult ETP-ALL ||FLT3 inhibitors are evaluated in the pre-clinical studies |
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
GATA3 encodes a transcription factor that is required for the development of T lymphocytes at multiple late differentiation steps . Silencing of GATA3 via hypermethylation has been observed in 33% of adult ETP-ALL in a study of 70 adult ETP-ALL patients .
Genes and Main Pathways Involved
|Gene; Genetic Alteration||Pathway||Pathophysiologic Outcome|
|EZH2, SUZ12, and EED; Inactivating mutations||Epigenetic regulation/Histone modification||cell maturation arrest|
|IL7R; Activating mutations||JAK/STAT signaling pathway||cell differentiation block|
Diagnostic Testing Methods
Clinical, morphological, and immunophenotypic findings are generally sufficient for diagnosis. ETP-ALL has distinct gene expression profile, however, this approach is not feasible in the current setting of routine diagnostic laboratories.
The prognosis of this disease entity was initially considered poor compared to other subtypes of T-ALL based on few small studies . However, more recent studies with larger patient cohorts suggested that the overall outcome with appropriate therapy appeared to not differ significantly from other subtypes .
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