HAEM5:Chronic myeloid leukaemia

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:Chronic Myeloid Leukemia (CML), BCR-ABL1 Positive.

(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)*

Jack Reid, MD (University of California, Irvine)

Mark Evans, MD (University of California, Irvine)

Fabiola Quintero-Rivera, MD (University of California, Irvine)

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	Myeloid proliferations and neoplasms
Family	Myeloproliferative neoplasms
Type	Myeloproliferative neoplasms
Subtype(s)	Chronic myeloid leukaemia

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)

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CML is the first cancer that is known to be linked to a specific genetic abnormality, namely the balanced chromosomal translocation known as Philadelphia Chromosome. A focal gene area of BCR (Breakpoint Cluster Region) from chromosome 22 is fused with another gene ABL (Tyrosine protein kinase ABL) that is located on chromosome 9. The chimeric oncogene BCR-ABL is the central to the pathology of CML because ABL carries a domain that is capable of phosphorylating tyrosine residues, activating a cascade of proteins that control the cell cycle. It was reported that 90% - 95% of the CML in chronic phase shows characteristic t(9;22)(q34;q11.2) reciprocal translocation that results in the Ph chromosome. This balanced translocation leads to the formation of the BCR/ABL fusion gene on chromosome 22 and a reciprocal ABL/BCR fusion gene on chromosome 9. Studies has shown that the latter gene ABL/BCR fusion gene does not seem to have any crucial role in CML and no ABL/BCR protein has been found.

Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Prevalence
t(9;22)(q34.1;q11.2)	3'ABL1 / 5'BCR	More than 90%

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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)

Diagnosis:

Currently four FDA approved tyrosine kinase inhibitors (TKIs) - imatinib, nilotinib, dasatinib and bosutinib - are the first line of treatment for patients with newly diagnosed CML in chronic phase (CML-CP). For many years, inhibitors of the specific BCR-ABL1 tyrosine kinase are considered to be the most effective targeted therapy. A subset of CML patients can demonstrate resistance to TKI therapy through mutations in ABL1 and other mechanisms. The culprit of the resistance to TKI therapy can be attributed to so-called leukemic stem cells (LSCs), pluripotent BCR-ABL1+ progenitors that are largely quiescent. Therefore, understanding of signaling pathways related to survival of LSCs may be helpful.

Prognosis: Acquired resistance to imatinib therapy , mostly with mutation in BCR-ABL kinase domain, is known to be associated with poor prognosis. Five prognostic factors were shown to be associated with major cytogenetic response: the absence of blasts in peripheral blood, a hemoglobin level of more than 12 g per deciliter, the presence of less than 5 percent blasts in marrow, a time from diagnosis of CML to start of treatment of less than one year, and a history of cytogenetic relapse during interferon therapy.

Therapeutic implication: Studies have shown that median survival

Complete cytogenetic  response is defined as 0% of Philadelphia-chromosome (Ph)-positive cells in metaphase in bone marrow.

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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:Genomic Gain/Loss/LOH

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Not Applicable.

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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 Aberrations / Patterns

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Atypical chronic myeloid leukemia (aCML) is a subtype of myelodysplastic/myeloproliferative neoplasm that lacks Philadelphia chromosome or rearrangements of PDGFRA, PDGFRB, or FGFR1. This hematological disorder has a considerable overlapping clinicopathological features with CML and CMML. It differs from CML by older median age, lower level of granulocytosis, multilineage dysplasia and lack of basophilia. Up until now, no cytogenetic changes have been associated with aCML. In peripheral blood smear, aCML typically shows granulocytic leukocytosis with striking neutrophil dysplasia (nuclear hyposegmentation and hypogranularity).

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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.

editv4:Gene Mutations (SNV/INDEL)

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A few genes were noted to be altered during the transformed stages of CML, namely TP53, RB1, MYC, CDKN2A, NRAS, KRAS, RUNX1, MECOM, TET2, CBL, ASXL1, IDH1 and IDH2.

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Epigenomic Alterations

Not Applicable.

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete 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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Image courtesy of Fabiola Quintero-Rivera, MD

Breakpoint Cluster Region protein (BCR) is encoded by BCR gene, located on chromosome 22. BCR protein has serine/threonine kinase activity. The protein is also a GTPase-activating protein for p21rac and other kinases. BCR protein is involved in the two main pathways: FGFR1 mutant receptor activation and G-protein signaling HRAS regulation pathway. BCR-associated genetic rearrangement gives rise to hematological disorders. The ABL1 gene is located on chromosome 9q34.12 and encodes for ABL1 protein, which was discovered to be a tyrosine kinase protein. Depending on the breakpoint of the BCR gene, the size of the fusion protein can vary:  p190bcr-abl, p210bcr-abl, and p230bcr-abl, leading to three different isoforms. BCR-ABL1 gene fusion encodes a chimeric protein, which is mostly 210 kDa(P210BCRABL1) with constitutive tyrosine-kinase activity, escaping the cytokine regulation and regulatory controls of many intracellular signaling pathways that are associated with proliferation, differentiation and apoptosis. Many of the target proteins that are affected by dimerization of constitutive kinase activity of BCR-ABL fusion protein include STAT, RAS, RAF, JUN kinase, MYC, AKT, and other transducers. It was shown that when CML progresses to the blastic crisis phase, a new additional mutation is acquired GSK3beta, which leads to the activation of beta-catenin, preventing myeloid cell lineages to mature.

Image courtesy of Fabiola Quintero-Rivera, MD

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Genetic Diagnostic Testing Methods

Majority of the patients with CML are initially diagnosed through a blood test - complete blood count - before clinical manifestations. Bone marrow aspirate and core biopsy are performed sequentially to further support the process of making diagnosis as well as assessing percentage of blasts and basophils. Histologic features of CML in the peripheral blood are helpful in deriving the CML diagnosis. Ancillary tests are performed to clinch the diagnosis: immunohistochemistry, flow cytometry, conventional cytogenetic analysis, FISH and molecular RT-PCR-based studies.

Cytogenetic testing is used in CML patients to monitor how patients are responding to the treatment by detecting the number of cells with the Philadelphia chromosome. In conjunction with cytogenetic testing, FISH and PCR are ordered to quantify treatment  monitoring processes in CML. FISH allows the detection of BCR-ABL gene, which is essentially considered to be more of a sensitive test compared to cytogenetic testing. PCR is performed to find BCR-ABL fusion gene and other molecular abnormalities.  PCR is very efficient because it can detect even one abnormal cell from approximately 1 million healthy cells. FISH can be used in rare cases where molecular transcripts are not detected.

Continuous monitoring is part of the standard of care in CML patients because it allows the clinicians to identify treatment failure, disease evolution and drug regimen adherence. Minimal residual disease monitoring is done by using RT-PCR.  Major molecular response (MMR) is the critical goal of CML treatment. Complete or deep molecular response is achieved when there is absence of BCR-ABL1 transcript or >4.5 logs below baseline level.

Familial Forms

Not Applicable.

Additional Information

Put your text here

Links

ABL1

BCR

References

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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 Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):

*Citation of this Page: “Chronic myeloid leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 03/24/2025, https://ccga.io/index.php/HAEM5:Chronic_myeloid_leukaemia.