Acute myeloid leukaemia with minimal differentiation
Haematolymphoid Tumours (5th ed.)
 | This page is under construction |
editHAEM5 Conversion NotesThis page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Acute Myeloid Leukemia (AML) with Minimal Differentiation.
(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. 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). 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)*
Celeste Eno, PhD, Cedars Sinai Medical Center, Los Angeles, Fabiola Quintero-Rivera, MD, FACMG, University of California Irvine
Cancer Category / Type
Cancer Sub-Classification / Subtype
Acute Myeloid Leukemia (AML) with minimal differentiation
Definition / Description of Disease
This is a distinct entity in the World Health Organization (WHO) classification system within the section of HAEM4:Acute Myeloid Leukemia (AML), Not Otherwise Specified[1]. This entity does not meet the criteria for inclusion in any of the other AML groups (i.e. AML with Recurrent Genetic Abnormalities, AML with Myelodysplasia-Related Changes, or Therapy-Related Myeloid Neoplasms).
• Recognized as a distinct entity in 1987[2]
• Rare subtype of acute leukemia without evidence of morphological or cytochemical myeloid differentiation
• Characterize as myeloid through use of immunohistochemistry, flow cytometry or EM cytochemistry
• More than 20% myeloid blasts in bone marrow or peripheral blood
• Less than 3% MPO or Sudan black B positivity by light-microscopic enzyme cytochemical analysis[3]
• No definitive evidence of lymphoid differentiation
Synonyms / Terminology
AML M0 (FAB classification)
Epidemiology / Prevalence
Approximately <5% AML cases. Affects all age groups though most patients are infants or older adults.
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 FeaturesThe content below was from the old template. Please incorporate above.• Patients present with evidence of bone marrow failure
• Anemia
• Thrombocytopenia
• Neutropenia
• Some patients present with leukocytosis and numerous circulating blasts
Sites of Involvement
Bone Marrow: hematopoietic stem cell
Morphologic Features
• Blasts are usually medium–sized with dispersed nuclear chromatin
• Markedly hypercellular bone marrow with poorly differentiated blasts
• Round or slightly indented nuclei with one or two nucleoli
• Agranular cytoplasm with variable degree of basinophila
• No Auer rods
• Residual normal population of maturing neutrophils may be present
• Less frequently, blasts are small, with more dispersed chromatin, inconspicuous nucleoli and scant cytoplasm resembling that of lymphoblasts.
• MPO and CAE and Sudan Black B staining is negative
Immunophenotype
Put your text here and fill in the table (Instruction: Can include references in the table)
| Finding | Marker |
|---|---|
| Positive (universal) | EXAMPLE CD1 |
| Positive (subset) | EXAMPLE CD2 |
| Negative (universal) | EXAMPLE CD3 |
| Negative (subset) | EXAMPLE CD4 |
editv4:ImmunophenotypeThe content below was from the old template. Please incorporate above.POSITIVE
• For any one of the myelomonocytic lineage antigens not expressed on normal B- or T-lymphoid cells: CD13, CD14, CD15, CD33, or CD64
• Or MPO positive detected by ultrastructural cytochemical analysis, immunohistochemical analysis or flow cytometric analysis[3]
• Most cases express early hematopoetic associated antigens: CD34, HLA-DR
• Approximately 60% of cases express CD33
• Blast cells express at mostly two myeloid-associated markers, CD13 and KIT (CD117)[4]
• 50% case Nuclear TdT is positive (may be of favorable prognostic significance)
• CD7 positive in 40% cases
• CD4 may have expression[5]
• Pediatric cases: CD33 bright
NEGATIVE:• Lack antigens associated with myeloid and monocytic maturation: CD11b, CD14,3 CD153, CD36, CD41, CD61, CD64 and CD65
• CD38 and/or HLA-DR may be decreased
• No monocytic differentiation: no coexpression of CD64 and CD36
• Blasts are negative for the B-cell and T-cell cytoplasmic lymphoid markers CD5, cCD3, cCD79a and cCD22
• MPO negative by cytochemistry, but maybe positive in some blasts by flow cytometry or immunohistochemistry.
• Glycophorin A
• Pediatric cases: Negative for TdT, CD34 and CD13 (weak)
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)The content below was from the old template. Please incorporate above.There is no recurrent rearrangements in this entity.
• t(7;12)(q36;p13), cytogenetically cryptic, leads to MNX1 deregulation and a poor prognosis.
- The morphology of cases is variable, but a significant portion is AML with minimal differentiation or without maturation most common in children[6][7].
- This translocation has also been reported in ALL
• t(10;11)(p12;q14) has an intermediate to poor prognosis[8] .
- Most cases show immature morphology.
- This translocation has also been reported in many other hematological malignancies[9].
Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence t(7;12)(q36;p13) 5’ HLXB9 – 3’ ETV6 der(12) Rare t(10;11)(p12;q14) 5’ CALM – 3’ AF10 Rare
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)
• Adverse outcome in children. May relate to a lack of more favorable AML cytogenetic abnormalities, such as t(8;21) and inv 16 and presence of high-risk abnormalities (i.e. chromosome 5)[10].
• Patients treated with only chemotherapy in conventional doses.
• Stem cell transplantation may contribute to a longer remission and prolongation of the survival[11].
• MDR1/p-170 protein is positive in blasts and mediates multidrug resistance in adults. This protein functions as a barrier, reducing intracellular concentrations of chemotherapeutics[12][13].
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/LOHThe content below was from the old template. Please incorporate above.• +4 sole; intermediate/poor prognosis
• +8[14]
• +10 sole; intermediate/poor prognosis[15]
• 11q gain MLL amplification; poor prognosis[14]
• +13 sole; poor prognosis[14][16][17] and associated with TdT expression[18]
• +14[14]
• del(11q)
• Loss and haploinsufficiency of ETV6 through deletion may be a leukemogenic step in AML-M0[7]
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 / PatternsThe content below was from the old template. Please incorporate above.• No specific chromosomal abnormality is identified
• Complex karyotype[14]
• Unbalanced abnormalities
• Most common: del(5q) or t(5q) and loss of chromosome 7 or del(7q)[14][16] the presence of these abnormalities would place the case in the category of AML with myelodysplasia-related changes per new WHO classification (2017).
• Near tetraploid karyotypes[11]
• Pediatric: Chromosome 5 aberrations, trisomy 21 and hypodiploidy more common in AML M0 than non-M0 counterparts[10]
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)The content below was from the old template. Please incorporate above.• Co-existence of gene mutations is common
• FLT3 Mutations: ITD and TKD, 16-22% of cases
• RAS: K-RAS and N-RAS
• IDH1 and IDH2 mutations[19]
• Loss and haploinsufficiency of ETV6 result of heterozygous/homozygous mutations may be a leukemogenic step in AML-M0[7]
• Mutations of RUNX1 occur in ~30% of cases[17], and correlates with the presence of trisomy 13 and increased FLT3 expression. De novo cases with RUNX1 mutations are now classified as the provisional entity of AML with mutated RUNX1 in the 2017 WHO[1].
Epigenomic Alterations
• High frequency of gene mutations in epigenetic modifiers implies that epigenetic deregulation and may lead to the pathogenesis of AML-M0[19].
• Histone acetylation and methylation patterns for patients with primary AML (all types) is ongoing[20].
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 |
Genetic Diagnostic Testing Methods
• Bone Marrow and peripheral blood examination for >20% blasts
• Cytochemical analysis, MPO and/or Sudan black B staining (undetectable - 3% positivity) for MPO
• Flow analysis: o Lack of expression of lymphoid-specific antigens cyCD3 for T cells and cyCD79 and cyCD22 for B cells o Positivity for any one of the myelomonocytic lineage antigens known not to be expressed on normal T-lymphoid cells (such as CD13, CD14, CD15, CD33, or CD64)
• Conventional G-banding cytogenetics
• FISH in cases of MLL (KMT2A) amplification and cryptic translocations involving ETV6
Familial Forms
Put your text here (Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.)
Additional Information
Differential Diagnosis: Acute Lymphoblastic Leukemia (more common), mixed phenotype acute leukemia, leukemic phase of large cell lymphoma (less common)
Links
Put your links here
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.)
- ↑ 1.0 1.1 Arber DA, et al., (2017). Acute myeloid leukaemia,NOS in WHO 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 Editors. IARC Press: Lyon, France, p156-158.
- ↑ Lee, M. S.; et al. (1987). "T-cell receptor gamma chain gene rearrangement in acute myelogenous leukemia--evidence for lymphoid lineage prematurity". Hematologic Pathology. 1 (2): 93–98. ISSN 0886-0238. PMID 2848796.
- ↑ 3.0 3.1 Kaleem, Z.; et al. (2001). "Diagnostic criteria for minimally differentiated acute myeloid leukemia (AML-M0). Evaluation and a proposal". American Journal of Clinical Pathology. 115 (6): 876–884. doi:10.1309/D2BR-C0V5-LEYD-HA2D. ISSN 0002-9173. PMID 11392885.
- ↑ Thalhammer-Scherrer, Renate; et al. (2002). "The immunophenotype of 325 adult acute leukemias: relationship to morphologic and molecular classification and proposal for a minimal screening program highly predictive for lineage discrimination". American Journal of Clinical Pathology. 117 (3): 380–389. doi:10.1309/C38D-D8J3-JU3E-V6EE. ISSN 0002-9173. PMID 11888077.
- ↑ Bennett, J. M.; et al. (1981). "The morphological classification of acute lymphoblastic leukaemia: concordance among observers and clinical correlations". British Journal of Haematology. 47 (4): 553–561. doi:10.1111/j.1365-2141.1981.tb02684.x. ISSN 0007-1048. PMID 6938236.
- ↑ Tosi, S.; et al. (2000). "t(7;12)(q36;p13), a new recurrent translocation involving ETV6 in infant leukemia". Genes, Chromosomes & Cancer. 29 (4): 325–332. doi:10.1002/1098-2264(2000)9999:99993.0.co;2-9. ISSN 1045-2257. PMID 11066076.
- ↑ 7.0 7.1 7.2 Silva, F. P. G.; et al. (2008). "ETV6 mutations and loss in AML-M0". Leukemia. 22 (8): 1639–1643. doi:10.1038/leu.2008.34. ISSN 1476-5551. PMID 18305557.
- ↑ Cancer Genome Atlas Research Network; et al. (2013). "Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia". The New England Journal of Medicine. 368 (22): 2059–2074. doi:10.1056/NEJMoa1301689. ISSN 1533-4406. PMC 3767041. PMID 23634996.
- ↑ Caudell, D.; et al. (2008). "The role of CALM-AF10 gene fusion in acute leukemia". Leukemia. 22 (4): 678–685. doi:10.1038/sj.leu.2405074. ISSN 1476-5551. PMC 2366104. PMID 18094714.
- ↑ 10.0 10.1 Barbaric, Draga; et al. (2007). "Minimally differentiated acute myeloid leukemia (FAB AML-M0) is associated with an adverse outcome in children: a report from the Children's Oncology Group, studies CCG-2891 and CCG-2961". Blood. 109 (6): 2314–2321. doi:10.1182/blood-2005-11-025536. ISSN 0006-4971. PMC 1852193. PMID 17158236.
- ↑ 11.0 11.1 Béné, M. C.; et al. (2001). "Acute myeloid leukaemia M0: haematological, immunophenotypic and cytogenetic characteristics and their prognostic significance: an analysis in 241 patients". British Journal of Haematology. 113 (3): 737–745. doi:10.1046/j.1365-2141.2001.02801.x. ISSN 0007-1048. PMID 11380465.
- ↑ Campos, L.; et al. (1992). "Correlation of MDR1/P-170 expression with daunorubicin uptake and sensitivity of leukemic progenitors in acute myeloid leukemia". European Journal of Haematology. 48 (5): 254–258. doi:10.1111/j.1600-0609.1992.tb01803.x. ISSN 0902-4441. PMID 1353726.
- ↑ Wuchter, C.; et al. (1999). "Clinical significance of CD95, Bcl-2 and Bax expression and CD95 function in adult de novo acute myeloid leukemia in context of P-glycoprotein function, maturation stage, and cytogenetics". Leukemia. 13 (12): 1943–1953. doi:10.1038/sj.leu.2401605. ISSN 0887-6924. PMID 10602414.
- ↑ 14.0 14.1 14.2 14.3 14.4 14.5 Klaus, Mirjam; et al. (2004). "Cytogenetic profile in de novo acute myeloid leukemia with FAB subtypes M0, M1, and M2: a study based on 652 cases analyzed with morphology, cytogenetics, and fluorescence in situ hybridization". Cancer Genetics and Cytogenetics. 155 (1): 47–56. doi:10.1016/j.cancergencyto.2004.03.008. ISSN 0165-4608. PMID 15527902.
- ↑ Johansson B and Harrison CJ (2015). Cancer Cytogenetics: Chromosomal and molecular genetic aberrations of tumor cells, 4th edition. Heim S and Mitelman F, Editors, Wiley-Blackwell: p62-84.
- ↑ 16.0 16.1 Cuneo, A.; et al. (1995). "Cytogenetic profile of minimally differentiated (FAB M0) acute myeloid leukemia: correlation with clinicobiologic findings". Blood. 85 (12): 3688–3694. ISSN 0006-4971. PMID 7780152.
- ↑ 17.0 17.1 Silva, Fernando P. G.; et al. (2007). "Trisomy 13 correlates with RUNX1 mutation and increased FLT3 expression in AML-M0 patients". Haematologica. 92 (8): 1123–1126. doi:10.3324/haematol.11296. ISSN 1592-8721. PMID 17650443.
- ↑ Patel, Keyur P.; et al. (2013). "TdT expression in acute myeloid leukemia with minimal differentiation is associated with distinctive clinicopathological features and better overall survival following stem cell transplantation". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 26 (2): 195–203. doi:10.1038/modpathol.2012.142. ISSN 1530-0285. PMC 5485410. PMID 22936064.
- ↑ 19.0 19.1 Kao, Hsiao-Wen; et al. (2014). "Gene mutation patterns in patients with minimally differentiated acute myeloid leukemia". Neoplasia (New York, N.Y.). 16 (6): 481–488. doi:10.1016/j.neo.2014.06.002. ISSN 1476-5586. PMC 4198802. PMID 25022553.
- ↑ Hellenbrecht A. ChIP- Chip microarrays to study the epigenome in leukemia. Available at: https://www.leukemia-net.org/content/leukemias/aml/aml_information/chip_microarrays/index_eng.html. Accessed June 20, 2018.
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: “Acute myeloid leukaemia with minimal differentiation”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/13/2023, https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_minimal_differentiation.