Early T-precursor lymphoblastic leukaemia / lymphoma

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Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification
This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Early T-Cell Precursor Lymphoblastic Leukemia.

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

Fei Yang, MD, FACMG, Kaiser Permanente Northwest

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category T-cell and NK-cell lymphoid proliferations and lymphomas
Family Precursor T-cell neoplasms
Type T-lymphoblastic leukaemia / lymphoma
Subtype(s) Early T-precursor lymphoblastic leukaemia / lymphoma

WHO Essential and Desirable Genetic Diagnostic Criteria

(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)

WHO Essential Criteria (Genetics)*
WHO Desirable Criteria (Genetics)*
Other Classification

*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.

Related Terminology

(Instructions: The table will have the related terminology from the WHO autocompleted.)

Acceptable
Not Recommended

Gene Rearrangements

Put your text here and fill in the table (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Driver Gene Fusion(s) and Common Partner Genes Molecular Pathogenesis Typical Chromosomal Alteration(s) Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE: ABL1 EXAMPLE: BCR::ABL1 EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1. EXAMPLE: t(9;22)(q34;q11.2) EXAMPLE: Common (CML) EXAMPLE: D, P, T EXAMPLE: Yes (WHO, NCCN) EXAMPLE:

The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).

EXAMPLE: CIC EXAMPLE: CIC::DUX4 EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5. EXAMPLE: t(4;19)(q25;q13) EXAMPLE: Common (CIC-rearranged sarcoma) EXAMPLE: D EXAMPLE:

DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).

EXAMPLE: ALK EXAMPLE: ELM4::ALK


Other fusion partners include KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1

EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18. EXAMPLE: N/A EXAMPLE: Rare (Lung adenocarcinoma) EXAMPLE: T EXAMPLE:

Both balanced and unbalanced forms are observed by FISH (add references).

EXAMPLE: ABL1 EXAMPLE: N/A EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways. EXAMPLE: N/A EXAMPLE: Recurrent (IDH-wildtype Glioblastoma) EXAMPLE: D, P, T
editv4:Chromosomal Rearrangements (Gene Fusions)
The content below was from the previous version of the page. Please incorporate above.

MEF2C (5q14) rearrangement or rearrangement involving MEF2C-related cofactors have been reported in about 50% of ETP-ALL cases[1], which have been validated in an independent ETP-ALL patient cohort[2]. 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 [3], 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 [3].

End of V4 Section

Individual Region Genomic Gain/Loss/LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)

Chr # Gain, Loss, Amp, LOH Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] Relevant Gene(s) Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE:

7

EXAMPLE: Loss EXAMPLE:

chr7

EXAMPLE:

Unknown

EXAMPLE: D, P EXAMPLE: No EXAMPLE:

Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).

EXAMPLE:

8

EXAMPLE: Gain EXAMPLE:

chr8

EXAMPLE:

Unknown

EXAMPLE: D, P EXAMPLE:

Common recurrent secondary finding for t(8;21) (add references).

EXAMPLE:

17

EXAMPLE: Amp EXAMPLE:

17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]

EXAMPLE:

ERBB2

EXAMPLE: D, P, T EXAMPLE:

Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.

editv4:Individual Region Genomic Gain/Loss/LOH
The content below was from the previous version of the page. Please incorporate above.

Currently there is no specific copy number alterations/LOH that is associated with ETP-ALL.

End of V4 Section

Characteristic Chromosomal or Other Global Mutational Patterns

Put your text here and fill in the table (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Chromosomal Pattern Molecular Pathogenesis Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE:

Co-deletion of 1p and 18q

EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). EXAMPLE: Common (Oligodendroglioma) EXAMPLE: D, P
EXAMPLE:

Microsatellite instability - hypermutated

EXAMPLE: Common (Endometrial carcinoma) EXAMPLE: P, T
editv4:Characteristic Chromosomal Patterns
The content below was from the previous version of the page. Please incorporate above.

Currently there is no specific chromosomal alteration that is characteristic for ETP-ALL.

End of V4 Section

Gene Mutations (SNV/INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Gene Genetic Alteration Tumor Suppressor Gene, Oncogene, Other Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

Diagnostic, Prognostic, and Therapeutic Significance - D, P, T   Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE:EGFR


EXAMPLE: Exon 18-21 activating mutations EXAMPLE: Oncogene EXAMPLE: Common (lung cancer) EXAMPLE: T EXAMPLE: Yes (NCCN) EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
EXAMPLE: TP53; Variable LOF mutations


EXAMPLE: Variable LOF mutations EXAMPLE: Tumor Supressor Gene EXAMPLE: Common (breast cancer) EXAMPLE: P EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations EXAMPLE: Activating mutations EXAMPLE: Oncogene EXAMPLE: Common (melanoma) EXAMPLE: T

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

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 [4]. More typical T-ALL mutations, such as NOTCH1 mutations and CDKN1/2 mutations are less frequent in ETP-ALL [5].

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 [6][7] core componenets of the PRC2: EZH2, SUZ12, and EED associated with slow response to chemotherapy [6] Ruxolitinib is evaluated in pre-clinical and clinical studies [8][9][4]
Components of PRC2: EZH2, SUZ12, EED; variable LOF mutations TSG 48% of pediatric ETP-ALL [7] BET inhibitors are evaluated in the pre-clinical studies [10]
FLT3; Activating mutations including ITD and TKD Oncogene 35% of adult ETP-ALL [11] FLT3 inhibitors are evaluated in the pre-clinical studies [11]

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.

Epigenomic Alterations

GATA3 encodes a transcription factor that is required for the development of T lymphocytes at multiple late differentiation steps [12]. Silencing of GATA3 via hypermethylation has been observed in 33% of adult ETP-ALL in a study of 70 adult ETP-ALL patients [13].

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

Genetic 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.

Familial Forms

Unknown

Additional Information

The prognosis of this disease entity was initially considered poor compared to other subtypes of T-ALL based on few small studies [14][15][16]. However, more recent studies with larger patient cohorts suggested that the overall outcome with appropriate therapy appeared to not differ significantly from other subtypes [17][18].

Links

N/A

References

  1. ↑ Homminga I, Pieters R, Langerak A, de Rooi J, Stubbs A, Verstegen M, et al. MEF2C as Novel Oncogene for Early T-Cell Precursor (ETP) Leukemia. Blood (2010) 116:9–9. doi: 10.1182/blood.V116.21.9.9
  2. ↑ Meijer M, Cordo V, Hagelaar R, Smits W, Meijerink J. Manipulating MEF2C: Discovering Novel Drugs to Target ETP-ALL. Blood (2021) 138 (Supplement 1): 3325. doi.org/10.1182/blood-2021-150176.
  3. ↑ Jump up to: 3.0 3.1 Noronha, Elda Pereira; et al. (2019). "T-lymphoid/myeloid mixed phenotype acute leukemia and early T-cell precursor lymphoblastic leukemia similarities with NOTCH1 mutation as a good prognostic factor". Cancer Management and Research. 11: 3933–3943. doi:10.2147/CMAR.S196574. ISSN 1179-1322. PMC 6504706. PMID 31118806.
  4. ↑ Jump up to: 4.0 4.1 Sin, Chun-Fung; et al. (2021). "Early T-Cell Precursor Acute Lymphoblastic Leukemia: Diagnosis, Updates in Molecular Pathogenesis, Management, and Novel Therapies". Frontiers in Oncology. 11: 750789. doi:10.3389/fonc.2021.750789. ISSN 2234-943X. PMC 8666570 Check |pmc= value (help). PMID 34912707 Check |pmid= value (help).
  5. ↑ Jain, Nitin; et al. (2016-04-14). "Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype". Blood. 127 (15): 1863–1869. doi:10.1182/blood-2015-08-661702. ISSN 1528-0020. PMC 4915808. PMID 26747249.
  6. ↑ Jump up to: 6.0 6.1 Kim, Rathana; et al. (2020-07). "Adult T-cell acute lymphoblastic leukemias with IL7R pathway mutations are slow-responders who do not benefit from allogeneic stem-cell transplantation". Leukemia. 34 (7): 1730–1740. doi:10.1038/s41375-019-0685-4. ISSN 1476-5551. PMID 31992840. Check date values in: |date= (help)
  7. ↑ Jump up to: 7.0 7.1 Zhang, Jinghui; et al. (2012-01-11). "The genetic basis of early T-cell precursor acute lymphoblastic leukaemia". Nature. 481 (7380): 157–163. doi:10.1038/nature10725. ISSN 1476-4687. PMC 3267575. PMID 22237106.
  8. ↑ Delgado-Martin, C.; et al. (2017-12). "JAK/STAT pathway inhibition overcomes IL7-induced glucocorticoid resistance in a subset of human T-cell acute lymphoblastic leukemias". Leukemia. 31 (12): 2568–2576. doi:10.1038/leu.2017.136. ISSN 1476-5551. PMC 5729333. PMID 28484265. Check date values in: |date= (help)
  9. ↑ Maude, Shannon L.; et al. (2015-03-12). "Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia". Blood. 125 (11): 1759–1767. doi:10.1182/blood-2014-06-580480. ISSN 1528-0020. PMC 4357583. PMID 25645356.
  10. ↑ Andrieu, Guillaume P.; et al. (2021-11-11). "PRC2 loss of function confers a targetable vulnerability to BET proteins in T-ALL". Blood. 138 (19): 1855–1869. doi:10.1182/blood.2020010081. ISSN 1528-0020. PMID 34125178 Check |pmid= value (help).
  11. ↑ Jump up to: 11.0 11.1 Neumann, Martin; et al. (2013). "FLT3 mutations in early T-cell precursor ALL characterize a stem cell like leukemia and imply the clinical use of tyrosine kinase inhibitors". PloS One. 8 (1): e53190. doi:10.1371/journal.pone.0053190. ISSN 1932-6203. PMC 3554732. PMID 23359050.
  12. ↑ Hosoya, Tomonori; et al. (2009-12-21). "GATA-3 is required for early T lineage progenitor development". The Journal of Experimental Medicine. 206 (13): 2987–3000. doi:10.1084/jem.20090934. ISSN 1540-9538. PMC 2806453. PMID 19934022.
  13. ↑ Fransecky, L.; et al. (2016-09-22). "Silencing of GATA3 defines a novel stem cell-like subgroup of ETP-ALL". Journal of Hematology & Oncology. 9 (1): 95. doi:10.1186/s13045-016-0324-8. ISSN 1756-8722. PMC 5034449. PMID 27658391.
  14. ↑ Coustan-Smith, Elaine; et al. (2009-02). "Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia". The Lancet. Oncology. 10 (2): 147–156. doi:10.1016/S1470-2045(08)70314-0. ISSN 1474-5488. PMC 2840241. PMID 19147408. Check date values in: |date= (help)
  15. ↑ Inukai, Takeshi; et al. (2012-02). "Clinical significance of early T-cell precursor acute lymphoblastic leukaemia: results of the Tokyo Children's Cancer Study Group Study L99-15". British Journal of Haematology. 156 (3): 358–365. doi:10.1111/j.1365-2141.2011.08955.x. ISSN 1365-2141. PMID 22128890. Check date values in: |date= (help)
  16. ↑ Ma, Meilin; et al. (2012-12). "Early T-cell precursor leukemia: a subtype of high risk childhood acute lymphoblastic leukemia". Frontiers of Medicine. 6 (4): 416–420. doi:10.1007/s11684-012-0224-4. ISSN 2095-0225. PMID 23065427. Check date values in: |date= (help)
  17. ↑ Patrick, Katharine; et al. (2014-08). "Outcome for children and young people with Early T-cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003". British Journal of Haematology. 166 (3): 421–424. doi:10.1111/bjh.12882. ISSN 1365-2141. PMID 24708207. Check date values in: |date= (help)
  18. ↑ Wood, Brent L.; et al. (2014-12-06). "T-Lymphoblastic Leukemia (T-ALL) Shows Excellent Outcome, Lack of Significance of the Early Thymic Precursor (ETP) Immunophenotype, and Validation of the Prognostic Value of End-Induction Minimal Residual Disease (MRD) in Children's Oncology Group (COG) Study AALL0434". Blood. 124 (21): 1–1. doi:10.1182/blood.V124.21.1.1. ISSN 0006-4971.

Notes

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*Citation of this Page: “Early T-precursor lymphoblastic leukaemia / lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 03/24/2025, https://ccga.io/index.php/HAEM5:Early_T-precursor_lymphoblastic_leukaemia_/_lymphoma.

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