HAEM5:Myeloid/lymphoid neoplasms with other tyrosine kinase fusion genes

Haematolymphoid Tumours (WHO Classification, 5th ed.)

(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)*

Put your text here (Rolando Garcia, PhD)

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	Myeloid proliferations and neoplasms
Family	Myeloid/lymphoid neoplasms
Type	Myeloid/lymphoid neoplasms with eosinophilia and defining gene rearrangement
Subtype(s)	Myeloid/lymphoid neoplasms with other tyrosine kinase fusion genes

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)*	Detection of a tyrosine kinase fusion gene not classified under specific unique entities (PDGFRA, PDGFRB, FGFR1, JAK2, FLT3, ETV6::ABL1).
WHO Desirable Criteria (Genetics)*	Cytogenetic translocation suggesting a potential involvement of a tyrosine kinase gene, with selection of a FISH break-apart probe or another molecular assay for confirmation.
Other Classification	Other desirable criteria: Presence of eosinophilia.

*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	Myeloid/lymphoid neoplasms with other tyrosine kinase fusion genes, Other and unspecified myeloproliferative neoplasms.
Not Recommended	Myeloid/lymphoid neoplasms with tyrosine kinase fusion genes (NOS).

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
FGFR2	ETV6::FGFR2	Fusion between exon 4 of ETV6 and exon 5 of FGFR2 (5′ to 3′ orientation).	Cryptic rearrangement detected by FISH involving chromosomes 10 and 12	Rare < 5%	D, P, T	Yes (WHO)	Myeloid / lymphoid acute leukemia. This fusion suggests abnormal FGFR2 expression. Aberrant The FGFR2 activation resulting from ETV6::FGFR2 may respond to FGFR1,2,3 tyrosine kinase inhibitors (TKIs). This rearrangement exhibited aggressive clinical behavior, demonstrating resistance to both conventional and intensive chemotherapy, as well as allogeneic stem cell transplantation. The prognosis remains unclear due to the limited number of cases.
LYN	ETV6::LYN	Fusion between exon 5 in ETV6 to exon 8 in LYN (5′ to 3′ orientation to produce an in-frame chimeric fusion)	Complex rearrangements involving chromosomes 8 and 12 [e.g. t(8;12)(q12;p13), ins(12;8)(p13;q11q21)]	Rare < 5%	D. P,T	Yes (WHO)	Acute myeloid leukemia / primary myelofibrosis/ T-lymphoblastic leukemia. Resistant to intensive chemotherapy or stem cell transplant, the disease progressed rapidly to terminal AML. Prognosis is not well defined due to the small number of cases.
NTRK3	ETV6::NTRK3	Fusion between ETV6 and NTRK3 (5′ to 3′ orientation)	t(12;15)(p13;q25)	Rare < 5%	T	Yes (WHO)	ETV6::NTRK3 is reported in multiple cancers but rare in acute lymphoblastic leukemia. The ETV6::NTRK3 responded to the ALK inhibitory crizotinib. Prognosis is not well defined due to the small number of cases.
ALK	RANBP2::ALK	exon 18 of RANBP2 and exon 20 of ALK (5′ to 3′ orientation). Leads to constitutive autophosphorylation of ALK tyrosine kinase and activating downstream signaling.	inv(2)(p23q13) / t(2;2)(p23;q13)	Rare < 5%	D, P, T	Yes (WHO)	Acute myelomonocytic leukemia/ myeloproliferative leukemia. Resistant to intensive chemotherapy and allogeneic SCT. Poor clinical outcome. Prognosis is not well defined due to the small number of cases.
RET	BCR::RET	Fusion between BCR exon 4 with the RET exon 12 (5′ to 3′ orientation). Aberrant expression of the kinase domain.	t(10;22)(q11;q11)	Rare <5%	D, P, T	Yes (WHO)	Associated with chronic myelomonocytic leukemia and monocytic differentiation. Sensitive to Sorafenib, an inhibitor to tyrosine kinase activity. The prognosis not well defined due to the limited number of cases.
RET	FGFR1OP::RET	Fusion between FGFR1OP exon 12 with RET exon 12 (5′ to 3′ orientation). Abnormal expression of the tyrosine kinase domain.	t(6;10)(q27;q11)	Rare <5%	D, P, T	Yes (WHO)	Associated with chronic myelomonocytic leukemia and monocytic differentiation. The prognosis remains unclear due to the limited number of cases.

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.

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

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.

Epigenomic Alterations

Put your text here

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

Genetic Diagnostic Testing Methods

Put your text here (Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.)

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

Put a link here or anywhere appropriate in this page (Instructions: Highlight the text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the wiki page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "http://www." portion.)

References

(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. 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. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted.)

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: “Myeloid/lymphoid neoplasms with other tyrosine kinase fusion genes”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 03/24/2025, https://ccga.io/index.php/HAEM5:Myeloid/lymphoid_neoplasms_with_other_tyrosine_kinase_fusion_genes.