B-Lymphoblastic Leukemia/Lymphoma with iAMP21

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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

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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

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


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)

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)

Characteristic Chromosomal Aberrations / Patterns

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]

Genomic Gain/Loss/LOH

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

Gene Mutations (SNV/INDEL)

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%
NF1 2%

Other Mutations

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

Epigenomics (Methylation)

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Genes and Main Pathways Involved


RAS pathway[9]

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).

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

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.

Familial Forms

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Other Information

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  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)


  1. Arber DA, et al., (2008). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p117-118.


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