Acute Myeloid Leukemia (AML) with Myelodysplasia-Related Changes

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Primary Author(s)*

Fei Yang, MD, FACMG
Oregon Health & Science University, Portland, OR

Cancer Category/Type

Acute Myeloid Leukemia

Cancer Sub-Classification / Subtype

Acute Myeloid Leukemia (AML) with Myelodysplasia-Related Changes

Definition / Description of Disease

Acute myeloid leukemia with myelodysplastic-related changes (AML-MRC) is an acute leukemia with 20% peripheral blood or bone marrow blasts with morphological features of myelodysplasia, or occurring in patients with a prior history of a MDS or MDS/MPN, or with MDS-related cytogenetic abnormalities, in the absence of prior history of cytotoxic or radiation therapy for an unrelated disease, and of recurrent cytogenetic aberrations or genetic abnormalities (mutated NPM1 or biallelic mutation of CEBPA) as described in Acute Myeloid Leukemia (AML) with Recurrent Genetic Abnormalities. This category has been retained in the 2016 revision to the World Health Organization (WHO) classification system with more refined criteria[1][2].

Synonyms / Terminology

Acute myeloid leukemia with multilineage dysplasia; acute myeloid leukemia with prior myelodysplastic syndrome

Epidemiology / Prevalence

AML-MRC is reported to account for 24-35% of all cases in AML. It occurs mainly in elderly patients and is rare in children[1][2].

Clinical Features

AML-MRC often presents with severe pancytopenia. Cases with 20-29% blasts may present a stable clinical course and slow progression similar to that of MDS than that of AML.

Sites of Involvement

Bone marrow.

Morphologic Features

  • Multilineage dysplasia: present in ≥50% of the cells in at least two haematopoietic cell lines.
  • Dysgranulopoiesis: neutrophils is characteristic of hypogranular cytoplasm, hyposegmented or bizarrely segmented nuclei.
  • Dyserythropoiesis: ring sideroblasts, cytoplasmic vacuoles, periodic acid-Schiff (PAS) positivity.
  • Dysmegakaryopoiesis: micromegakaryocytes, normal- or large-sized megakaryocytes with non-lobated or multiple nuclei.


Immunophenotyping results are variable due to the heterogeneity of the underlying genetic changes.

  • Myeloblasts have an expression of CD34, CD117, increased expression in CD14, variable expression in panmyeloid markers (CD13, CD33).
  • Background granulocytic cells may have higher CD33 expression, and under-expression of CD45, CD11b, and CD15.
  • Background monocytes have lower expression of CD14, CD56, and CD45.
Finding Marker
Positive (universal) EXAMPLE CD1
Positive (subset) EXAMPLE CD2
Negative (universal) EXAMPLE CD3
Negative (subset) EXAMPLE CD4

Chromosomal Rearrangements (Gene Fusions)

Balanced translocations are less common in AML-MRC, and often involve 5q32-33 and 11q23.3.

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence
t(3;5)(q25.3;q35.1) 5'NPM1/3'MLF1[3] der(5) unknown
t(11;16)(q23;p13.3) 5'KMT2A/3'CREBBP or 5'CREBBP/3'KMT2A[4] der(11) or der(16) unknown
t(2;11)(p21;q23.3) KMT2A rearrangement, partner gene unknown[5] unknown unknown
t(2;11)(p21;q23.3) MiR-125b-1 overexpression[6] der(11) unknown

Characteristic Chromosomal Aberrations / Patterns

Cytogenetic abnormalities sufficient for the diagnosis of AML-MRC when ≥20% peripheral blood or bone marrow blasts are present and prior therapy has been excluded:

Complex karyotype (3 or more abnormalities)

Unbalanced abnormalities:
Loss of chromosome 7 or del(7q)
del(5q) or t(5q)
Isochromosome 17q or t(17p)
Loss of chromosome 13 or del(13q)
del(12p) or t(12p)

Balanced abnormalities:

Genomic Gain/Loss/LOH

Genomic copy number gain or loss have not been described in AML-MRC currently. There is a case report describing isochromosome 17q and LOH in a patient with AML-MRC, whose clinical presentation involved extreme thrombocytosis[7].

Chromosome Number Gain/Loss/Amp/LOH Region
17 LOH chr17:59,000,001-159,138,663

Gene Mutations (SNV/INDEL)

Somatic genetic mutations commonly found in AML or MDS have been reported in AML-MRC. There are no characteristic genetic mutations fully specific for this entity. The most frequently mutated genes reported in AML-MRC are listed below.

Gene Mutation Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence (COSMIC/TCGA/Other)
TP53 Missense, nonsense, frameshift Tumor Suppressor LOF 22%
ASXL1 Frameshift, nonsense, missense Tumor Suppressor LOF 21-35%
U2AF1 Missense Oncogene GOF 16%
SF3B1 Missense Oncogene GOF 5.8%

Other Mutations

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

Epigenomics (Methylation)

Epigenetic aberration has not been described in AML-MRC currently.

Genes and Main Pathways Involved

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Diagnostic Testing Methods

Conventional chromosome analysis; FISH with MDS and AML panel; molecular genetic analysis for mutations such as targeted Next-generation sequencing (NGS) panel.

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)


  • FCI assessment of granulocytes and monocytes, in addition to blasts, may be valuable in aid distinguishing AML-MRC from AML-NOS[8].
  • Characteristic cytogenetic aberrations mentioned above are sufficient for the diagnosis of AML-MRC in the context of other criteria being met[1][2].
  • Differential diagnosis are MDS with excess blasts, pure erythroid leukemia, acute megakaryoblastic leukemia and AML-NOS[1][2].


  • AML-MRC generally has a poor prognosis with a lower rate of complete remission than in other AML subtypes[1][2].
  • TP53 mutations are associated with a complex karyotype and an even worse prognosis in this entity[9][10][11].
  • ASXL1 mutations are more frequent in AML-MRC, and are associated with a higher proportion of marrow dysgranulopoiesis and inferior 2-year overall survival[9][10].
  • Mutations in spliceosome gene U2AF1 are associated with trilineage morphologic dysplasia, absence of clinical remission, poor overall survival and poor disease-free survival[11].

Familial Forms

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Other Information

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  1. 1.0 1.1 1.2 1.3 1.4 Arber, Daniel A.; et al. (2016). "The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia". Blood. 127 (20): 2391–2405. doi:10.1182/blood-2016-03-643544. ISSN 1528-0020. PMID 27069254.
  2. 2.0 2.1 2.2 2.3 2.4 Arber DA, et al., (2017). Acute myeloid leukaemia 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, p160-161.
  3. Arber, Daniel A.; et al. (2003). "Detection of NPM/MLF1 fusion in t(3;5)-positive acute myeloid leukemia and myelodysplasia". Human Pathology. 34 (8): 809–813. doi:10.1016/s0046-8177(03)00251-x. ISSN 0046-8177. PMID 14506644.
  4. Zhang, Yanming; et al. (2004). "Characterization of genomic breakpoints in MLL and CBP in leukemia patients with t(11;16)". Genes, Chromosomes & Cancer. 41 (3): 257–265. doi:10.1002/gcc.20077. ISSN 1045-2257. PMID 15334549.
  5. Fleischman, E. W.; et al. (1999). "MLL is involved in a t(2;11)(p21;q23) in a patient with acute myeloblastic leukemia". Genes, Chromosomes & Cancer. 24 (2): 151–155. ISSN 1045-2257. PMID 9885982.
  6. Bousquet, Marina; et al. (2008). "Myeloid cell differentiation arrest by miR-125b-1 in myelodysplastic syndrome and acute myeloid leukemia with the t(2;11)(p21;q23) translocation". The Journal of Experimental Medicine. 205 (11): 2499–2506. doi:10.1084/jem.20080285. ISSN 1540-9538. PMC 2571925. PMID 18936236.
  7. You, Eunkyoung; et al. (2015). "A novel case of extreme thrombocytosis in acute myeloid leukemia associated with isochromosome 17q and copy neutral loss of heterozygosity". Annals of Laboratory Medicine. 35 (3): 366–369. doi:10.3343/alm.2015.35.3.366. ISSN 2234-3814. PMC 4390708. PMID 25932448.
  8. Weinberg, Olga K.; et al. (2017). "Diagnostic work-up of acute myeloid leukemia". American Journal of Hematology. 92 (3): 317–321. doi:10.1002/ajh.24648. ISSN 1096-8652. PMID 28066929.
  9. 9.0 9.1 Devillier, Raynier; et al. (2015). "Role of ASXL1 and TP53 mutations in the molecular classification and prognosis of acute myeloid leukemias with myelodysplasia-related changes". Oncotarget. 6 (10): 8388–8396. doi:10.18632/oncotarget.3460. ISSN 1949-2553. PMC 4480760. PMID 25860933.
  10. 10.0 10.1 Devillier, Raynier; et al. (2012). "Acute myeloid leukemia with myelodysplasia-related changes are characterized by a specific molecular pattern with high frequency of ASXL1 mutations". American Journal of Hematology. 87 (7): 659–662. doi:10.1002/ajh.23211. ISSN 1096-8652. PMID 22535592.
  11. 11.0 11.1 Ohgami, Robert S.; et al. (2015). "Next-generation sequencing of acute myeloid leukemia identifies the significance of TP53, U2AF1, ASXL1, and TET2 mutations". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 28 (5): 706–714. doi:10.1038/modpathol.2014.160. ISSN 1530-0285. PMC 5436901. PMID 25412851.


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