B-lymphoblastic leukaemia/lymphoma with iAMP21

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Haematolymphoid Tumours (5th ed.)

editHAEM5 Conversion Notes
This page was converted to the new template on 2023-11-03. The original page can be found at HAEM4:B-Lymphoblastic Leukemia/Lymphoma with iAMP21.

Primary Author(s)*

Holli M. Drendel, PhD, FACMGG, Carolinas Pathology Group, Charlotte

Cancer Category/Type

B-lymphoblastic leukemia/lymphoma

Cancer Sub-Classification / Subtype

B-lymphoblastic leukemia/lymphoma with iAMP21

Definition / Description of Disease

Intrachromosomal amplification of chromosome 21 (iAMP21) is a neoplasm of lymphoblasts that are of the B-cell lineage. It is characterized by amplification of the RUNX1 gene at 21q22.3 on a structurally abnormal chromosome 21. Amplification is defined as ≥5 copies of RUNX1 detected by FISH or ≥3 copies of RUNX1 on a single abnormal chromosome 21.[1]

Synonyms / Terminology

Put your text here (Instructions: Include currently used terms and major historical ones, adding “(historical)” after the latter.)

Epidemiology / Prevalence

iAMP21 is observed most often in the older pediatric group (median age of 9 years, with a range of 2-30 years). It accounts for ~2% of B-ALL cases including ~2% of standard-risk and 3% of high-risk patients. The incidence in adult B-ALL has not been established; however, it appears to be less prevalent than in the pediatric population.[2]

Further, patients carrying a rob(15;21)(q10;q10) have an ~2700-fold increased risk of developing iAMP21 ALL compared to the general population. Additionally, patients with a constitutional ring chromosome 21, r(21), may potentially be predisposed to iAMP21 ALL.[2]

Clinical Features

Put your text here and fill in the table (Instruction: Can include references in the table)

Signs and Symptoms EXAMPLE Asymptomatic (incidental finding on complete blood counts)

EXAMPLE B-symptoms (weight loss, fever, night sweats)

EXAMPLE Fatigue

EXAMPLE Lymphadenopathy (uncommon)

Laboratory Findings EXAMPLE Cytopenias

EXAMPLE Lymphocytosis (low level)


editv4:Clinical Features
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Patients tend to present with a low platelet count and low WBC count (<50,000/µl). ~50% of cases are classified as high-risk based on an age of ≥10 years.[3]

Sites of Involvement

Bone Marrow and peripheral blood

Morphologic Features

There are no unique morphological or cytochemical features that distinguish this entity from other types of ALL.[1]

Cytogenetic morphology of the abnormal chromosome 21 can vary markedly between patients.[4]

 
iAMP21 in a ring formation; Courtesy of Fullerton Genetics Lab


Immunophenotype

No detailed information is known, other than these cases occur exclusively in B-ALL.[1]

Finding Marker
Positive (universal) EXAMPLE CD1
Positive (subset) EXAMPLE CD2
Negative (universal) EXAMPLE CD3
Negative (subset) EXAMPLE CD4

Chromosomal Rearrangements (Gene Fusions)

Put your text here and fill in the table

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE t(9;22)(q34;q11.2) EXAMPLE 3'ABL1 / 5'BCR EXAMPLE der(22) EXAMPLE 20% (COSMIC)

EXAMPLE 30% (add reference)

Yes No Yes 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).


editv4:Chromosomal Rearrangements (Gene Fusions)
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Some rearrangements have been seen as secondary abnormalities.

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence
del(X)(p22.33p22.33)/del(Y)(p11.32p11.32) P2RY8-CRLF2 der(X)/der(Y)
t(12;21)(p13.2;q22.1) ETV6-RUNX1 der(21)
t(9;22)(q34;q11.2) BCR-ABL1 der(22)


editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).
Please incorporate this section into the relevant tables found in:
  • Chromosomal Rearrangements (Gene Fusions)
  • Individual Region Genomic Gain/Loss/LOH
  • Characteristic Chromosomal Patterns
  • Gene Mutations (SNV/INDEL)

Pediatric iAMP21 has been associated with a poor outcome. It displays an increased rate of relapse when treated on standard protocols. Further, the event-free survival and overall survival were significantly worse for individuals with the iAMP21 and standard-risk B-ALL, but not significant in individuals with iAMP21 and high-risk B-ALL.

Because of the unique nature of the iAMP21 abnormality, cases that present with additional genomic lesions that may suggest another category, such as a CRLF2 rearrangement, should still be classified as B-ALL with iAMP21.

Individual Region Genomic Gain/Loss/LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.)

Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE

7

EXAMPLE Loss EXAMPLE

chr7:1- 159,335,973 [hg38]

EXAMPLE

chr7

Yes Yes 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 reference).

EXAMPLE

8

EXAMPLE Gain EXAMPLE

chr8:1-145,138,636 [hg38]

EXAMPLE

chr8

No No No EXAMPLE

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

editv4:Genomic Gain/Loss/LOH
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In ~80% of iAMP21 B-ALL cases, recurrent secondary abnormalities, both chromosomal and molecular, have been documented. Deletions involving particular genes such as; IKZF1, CDKN2A/B, PAX5, SH2B3, ETV6 and RB1 have also been observed.

Chromosome Number Gain/Loss/Amp/LOH
X Gain
10 Gain
14 Gain
7/7q Loss
11q Loss

Characteristic Chromosomal Patterns

Put your text here (EXAMPLE PATTERNS: 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)

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE

Co-deletion of 1p and 18q

Yes No No EXAMPLE:

See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns
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Characteristic iAMP21 CMA; Courtesy of Fullerton Genetics Lab

iAMP21 cases have a characteristic pattern that is both complex and variable. This pattern comprises multiple regions of gain, amplification and deletion. Further, it often is accompanied by a terminal deletion of 21q. Interestingly, RUNX1 amplification is not always intrachromosomal.[5][6]

The formation of iAMP21 is considered to be due to breakage-fusion-bridge cycles followed by chromothripsis and other complex structural rearrangements of chromosome 21. Studies, molecular and cytogenetic, have elucidated a common 5.1 Mb region that includes the RUNX1 gene. This is part of the critical region consistently amplified (chr21:32.8-37.9 Mb, GRCh37/hg19). However, even though RUNX1 is included in the amplified region, there has not yet been any conclusive evidence that RUNX1 is critical in the pathogenesis of disease given that it is not overexpressed in some individuals with this abnormality.[2][7][8]

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 and common as well either disease defining and/or clinically significant. Can include references 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.)

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
EXAMPLE: TP53; Variable LOF mutations

EXAMPLE:

EGFR; Exon 20 mutations

EXAMPLE: BRAF; Activating mutations

EXAMPLE: TSG EXAMPLE: 20% (COSMIC)

EXAMPLE: 30% (add Reference)

EXAMPLE: IDH1 R123H EXAMPLE: EGFR amplification EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).


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.


editv4:Gene Mutations (SNV/INDEL)
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In a 2016 paper, it was shown that in the iAMP21-ALL exome, the mutations were more commonly transitions (for example: C>T) than transversions or indels.[2][9] Frequently, mutations in the RAS signaling pathway have been observed. Interestingly, these mutations were observed to coexist in patterns ranging from 2-3 mutated genes to 2-4 mutations in the same gene in one sample. Further, the FLT3-ITD was more prevalent in iAMP21-ALL.[9]

Gene Mutation Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence (COSMIC/TCGA/Other)
NRAS 45%
KRAS 18%
FLT3 20%
PTPN11 11%
BRAF 2%
NF1 2%

Other Mutations

Type Gene/Region/Other
Concomitant Mutations EXAMPLE IDH1 R123H
Secondary Mutations EXAMPLE Trisomy 7
Mutually Exclusive EXAMPLE EGFR Amplification

Epigenomic Alterations

Put your text here

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Can include references in the table.)

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations EXAMPLE: MAPK signaling EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations EXAMPLE: Cell cycle regulation EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations EXAMPLE:  Histone modification, chromatin remodeling EXAMPLE:  Abnormal gene expression program
editv4:Genes and Main Pathways Involved
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RUNX1

RAS pathway[9]

Genetic Diagnostic Testing Methods

Different methodologies are able to detect the iAMP21, such as:

  • Fluorescence in situ hybridization (FISH) utilizing the probe set for the t(12;21)
  • Conventional chromosome analysis
  • Multiplex ligation-dependent probe amplification (MLPA)
  • Chromosomal microarray (CMA)
  • Next generation sequencing (NGS).

Familial Forms

Put your text here (Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.)

Additional Information

Put your text here

Links

RUNX1

Put your links here (use "Link" icon at top of page)

References

(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference.)

  1. 1.0 1.1 1.2 Borowitz MJ, et al., (2017). B-Lymphoblastic leukaemia/lymphoma with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France.
  2. 2.0 2.1 2.2 2.3 Akkari, Yassmine M. N.; et al. (05 2020). "Evidence-based review of genomic aberrations in B-lymphoblastic leukemia/lymphoma: Report from the cancer genomics consortium working group for lymphoblastic leukemia". Cancer Genetics. 243: 52–72. doi:10.1016/j.cancergen.2020.03.001. ISSN 2210-7762. PMID 32302940 Check |pmid= value (help). Check date values in: |date= (help)
  3. Harrison, Christine J. (2015-02-26). "Blood Spotlight on iAMP21 acute lymphoblastic leukemia (ALL), a high-risk pediatric disease". Blood. 125 (9): 1383–1386. doi:10.1182/blood-2014-08-569228. ISSN 1528-0020. PMID 25608562.
  4. Harewood, L.; et al. (2003-03). "Amplification of AML1 on a duplicated chromosome 21 in acute lymphoblastic leukemia: a study of 20 cases". Leukemia. 17 (3): 547–553. doi:10.1038/sj.leu.2402849. ISSN 0887-6924. PMID 12646943. Check date values in: |date= (help)
  5. Arber, Daniel A. (04 2019). "The 2016 WHO classification of acute myeloid leukemia: What the practicing clinician needs to know". Seminars in Hematology. 56 (2): 90–95. doi:10.1053/j.seminhematol.2018.08.002. ISSN 1532-8686. PMID 30926096. Check date values in: |date= (help)
  6. Johnson, Ryan C.; et al. (2015-07). "Cytogenetic Variation of B-Lymphoblastic Leukemia With Intrachromosomal Amplification of Chromosome 21 (iAMP21): A Multi-Institutional Series Review". American Journal of Clinical Pathology. 144 (1): 103–112. doi:10.1309/AJCPLUYF11HQBYRB. ISSN 1943-7722. PMID 26071468. Check date values in: |date= (help)
  7. Rand, Vikki; et al. (2011-06-23). "Genomic characterization implicates iAMP21 as a likely primary genetic event in childhood B-cell precursor acute lymphoblastic leukemia". Blood. 117 (25): 6848–6855. doi:10.1182/blood-2011-01-329961. ISSN 1528-0020. PMID 21527530.
  8. Hunger, Stephen P.; et al. (2012-05-10). "Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 30 (14): 1663–1669. doi:10.1200/JCO.2011.37.8018. ISSN 1527-7755. PMC 3383113. PMID 22412151.
  9. 9.0 9.1 9.2 Ryan, S. L.; et al. (09 2016). "The role of the RAS pathway in iAMP21-ALL". Leukemia. 30 (9): 1824–1831. doi:10.1038/leu.2016.80. ISSN 1476-5551. PMC 5017527. PMID 27168466. Check date values in: |date= (help)

Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome. *Citation of this Page: “B-lymphoblastic leukaemia/lymphoma with iAMP21”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 11/3/2023, https://ccga.io/index.php/HAEM5:B-lymphoblastic_leukaemia/lymphoma_with_iAMP21.