Myeloid/lymphoid neoplasm with PDGFRA rearrangement

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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:Myeloid/Lymphoid Neoplasms with PDGFRA Rearrangement.

(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)*

Jay Alden, DO

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 neoplasm with PDGFRA rearrangement

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)
The content below was from the old template. Please incorporate above.
Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Prevalence
Cryptic del(4)(q12) FIP1L1-PDGFRA Majority
T(1;4) (q44;q12) FIP1L1-PDGFRA Rare [1]
T(4;10)(q12;p11.1-p11.2) FIP1L1-PDGFRA Rare [2]
T(4;22)(q12;q11.2) BCR-PDGFRA At least 9 cases [3][4][5][6]
T(2;4)(p24;q12) STRN-PDGFRA At least 1 case [7]
T(4;12)(q12;p13.2) ETV6-PDGFRA At least 1 case [7]
ins(9;4)(q33;q12q25) CDK5RAP2-PDGFRA At least 1 case [8]
T(4;10)(q12;q23.3) TNKS2-PDGFRA At least 1 case [9]
End of V4 Section


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)

The responsiveness of F/P associated myeloid/lymphoid neoplasms to imatinib mesylate is well documented [10]. Adverse outcomes are typically related to late presentation, where irreversible organ damage precedes diagnosis, or when the disease is diagnosed in an accelerated phase when complications are more likely. Induction dosing of imatinib ranges from 100-400 mg daily, with much lower maintenence dosing recommended to prevent relapse [11] [12]. Complete hematologic and molecular remission is observed in nearly all patients taking imatinib, usually within 3 months. [13] [14] [15] Imatinib maintains efficacy in accelerated or blast phase disease, and resistance is rare [16] [17].

End of V4 Section

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
editv4:Characteristic Chromosomal Aberrations / Patterns
The content below was from the old template. Please incorporate above.

Cytogenetic studies are usually normal though trisomy of chromosome 8 has been described, and may represent disease evolution [18].

End of V4 Section

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)
The content below was from the old template. Please incorporate above.

An activating point mutation in PDGFRA has also been described [19].

End of V4 Section

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
editv4:Genes and Main Pathways Involved
The content below was from the old template. Please incorporate above.

the F/P tyrosine kinase is thought to become constitutively active in the setting of PDGRA juxtamembrane interruption as breakpoints in the PDGRA gene are tightly clustered, resulting in the removal of a portion of the juxtamembrane domain and activation of the kinase domain upon rearrangement. The role of the FIP1L1 in the neoplastic process is thought to be less significant. [20] The eosinophilic proliferation observed in these patients is thought to result from multiple signalling pathways including phosphoinositol 3-kinase, ERK 1/2 and STAT5, though the precise mechanism remains elusive. [21][22]

End of V4 Section

Genetic Diagnostic Testing Methods

Myeloid/lymphoid neoplasms with PDGFRA are diagnosed with a combination of morphologic, immunophenotypic and genomic modalities; typically with a bone marrow biopsy and peripheral blood smear review, preferably drawn prior to administration of high dose corticosteroids. Additional studies performed at the time of workup include CBC to quantify any abnormalities in other cell lines, tests of hepatic and renal function, troponin for evidence of myocarditis, vitamin B12, serum tryptase, antineutrophil cytoplasmic antibodies, and a high resolution chest CT for evidence of pulmonary involvement. [23] The diagnosis is made when the F/P fusion gene or a variant fusion gene with rearrangement of PDGFRA or an activating mutation of PDGFRA is identified in the setting of a myeloid or lymphoid neoplasm, usually with prominent eosinophilia [18].

The F/P fusion gene can be detected by reverse transcriptase PCR (RT-PCR) [1], or the deletion can be detected using a probe for the CHIC2 gene, or with a break apart probe encompassing FIP1L1 and PDGFRA. [18]

Familial Forms

Put your text here (Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.)

Additional Information

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Links

PDGFRA

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.)

  1. ↑ Jump up to: 1.0 1.1 Cools, Jan; et al. (2003). "A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome". The New England Journal of Medicine. 348 (13): 1201–1214. doi:10.1056/NEJMoa025217. ISSN 1533-4406. PMID 12660384.
  2. ↑ Tashiro, Haruko; et al. (2006). "Molecular analysis of chronic eosinophilic leukemia with t(4;10) showing good response to imatinib mesylate". International Journal of Hematology. 83 (5): 433–438. doi:10.1532/IJH97.05180. ISSN 0925-5710. PMID 16787876.
  3. ↑ Baxter, E. Joanna; et al. (2002). "The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA". Human Molecular Genetics. 11 (12): 1391–1397. doi:10.1093/hmg/11.12.1391. ISSN 0964-6906. PMID 12023981.
  4. ↑ Van Etten, Richard A.; et al. (2006). "Distinct Leukemogenic Activity and Imatinib Responsiveness of a BCR-PFGFRα Fusion Tyrosine Kinase". Blood. 108 (11): 3634–3634. doi:10.1182/blood.V108.11.3634.3634. ISSN 0006-4971.
  5. ↑ Safley, Anne Michele; et al. (2004). "Molecular and cytogenetic characterization of a novel translocation t(4;22) involving the breakpoint cluster region and platelet-derived growth factor receptor-alpha genes in a patient with atypical chronic myeloid leukemia". Genes, Chromosomes & Cancer. 40 (1): 44–50. doi:10.1002/gcc.20014. ISSN 1045-2257. PMID 15034867.
  6. ↑ Trempat, Pascal; et al. (2003). "Chronic myeloproliferative disorders with rearrangement of the platelet-derived growth factor alpha receptor: a new clinical target for STI571/Glivec". Oncogene. 22 (36): 5702–5706. doi:10.1038/sj.onc.1206543. ISSN 0950-9232. PMID 12944919.
  7. ↑ Jump up to: 7.0 7.1 Curtis, Claire E.; et al. (2007). "Two novel imatinib-responsive PDGFRA fusion genes in chronic eosinophilic leukaemia". British Journal of Haematology. 138 (1): 77–81. doi:10.1111/j.1365-2141.2007.06628.x. ISSN 0007-1048. PMID 17555450.
  8. ↑ Walz, Christoph; et al. (2006). "Transient response to imatinib in a chronic eosinophilic leukemia associated with ins(9;4)(q33;q12q25) and a CDK5RAP2-PDGFRA fusion gene". Genes, Chromosomes & Cancer. 45 (10): 950–956. doi:10.1002/gcc.20359. ISSN 1045-2257. PMID 16845659.
  9. ↑ Chalmers, Z. R.; et al. (2015). "Comprehensive genomic profiling identifies a novel TNKS2-PDGFRA fusion that defines a myeloid neoplasm with eosinophilia that responded dramatically to imatinib therapy". Blood Cancer Journal. 5: e278. doi:10.1038/bcj.2014.95. ISSN 2044-5385. PMC 4349257. PMID 25658984.
  10. ↑ Shomali, William; et al. (2019). "World Health Organization-defined eosinophilic disorders: 2019 update on diagnosis, risk stratification, and management". American Journal of Hematology. 94 (10): 1149–1167. doi:10.1002/ajh.25617. ISSN 1096-8652. PMID 31423623.
  11. ↑ Baccarani, Michele; et al. (2007). "The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRalpha-positive hypereosinophilic syndrome. Results of a multicenter prospective study". Haematologica. 92 (9): 1173–1179. doi:10.3324/haematol.11420. ISSN 1592-8721. PMID 17666373.
  12. ↑ Jovanovic, Jelena V.; et al. (2007). "Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia". Blood. 109 (11): 4635–4640. doi:10.1182/blood-2006-10-050054. ISSN 0006-4971. PMID 17299092.
  13. ↑ Baccarani, Michele; et al. (2007). "The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRalpha-positive hypereosinophilic syndrome. Results of a multicenter prospective study". Haematologica. 92 (9): 1173–1179. doi:10.3324/haematol.11420. ISSN 1592-8721. PMID 17666373.
  14. ↑ Quéméneur, Thomas; et al. (2013). "Systemic vasculitis during the course of systemic sclerosis: report of 12 cases and review of the literature". Medicine. 92 (1): 1–9. doi:10.1097/MD.0b013e31827781fd. ISSN 1536-5964. PMC 5370746. PMID 23263715.
  15. ↑ Helbig, Grzegorz; et al. (2008). "A single weekly dose of imatinib is sufficient to induce and maintain remission of chronic eosinophilic leukaemia in FIP1L1-PDGFRA-expressing patients". British Journal of Haematology. 141 (2): 200–204. doi:10.1111/j.1365-2141.2008.07033.x. ISSN 1365-2141. PMID 18307562.
  16. ↑ Legrand, Fanny; et al. (2013). "The Spectrum of FIP1L1-PDGFRA-Associated Chronic Eosinophilic Leukemia: New Insights Based on a Survey of 44 Cases". Medicine. 92 (5): e1–e9. doi:10.1097/MD.0b013e3182a71eba. ISSN 1536-5964. PMC 4553979. PMID 23982058.
  17. ↑ Lierman, E.; et al. (2009). "FIP1L1-PDGFRalpha D842V, a novel panresistant mutant, emerging after treatment of FIP1L1-PDGFRalpha T674I eosinophilic leukemia with single agent sorafenib". Leukemia. 23 (5): 845–851. doi:10.1038/leu.2009.2. ISSN 1476-5551. PMID 19212337.
  18. ↑ Jump up to: 18.0 18.1 18.2 Bain BJ, et al., (2017). Myeloid/lymphoid neoplasms with PDGFRA rearrangement 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, p73-75.
  19. ↑ Elling, Christian; et al. (2011). "Novel imatinib-sensitive PDGFRA-activating point mutations in hypereosinophilic syndrome induce growth factor independence and leukemia-like disease". Blood. 117 (10): 2935–2943. doi:10.1182/blood-2010-05-286757. ISSN 1528-0020. PMID 21224473.
  20. ↑ J. Cools; et al. (2008). "Five years since the discovery of FIP1L1–PDGFRA : what we have learned about the fusion and other molecularly defined eosinophilias". Leukemia. 22 (11): 1999–2010. doi:10.1038/leu.2008.287. ISSN 1476-5551.
  21. ↑ Cools, Jan; et al. (2003). "A Tyrosine Kinase Created by Fusion of the PDGFRA and FIP1L1 Genes as a Therapeutic Target of Imatinib in Idiopathic Hypereosinophilic Syndrome". New England Journal of Medicine. 348 (13): 1201–1214. doi:10.1056/NEJMoa025217. ISSN 0028-4793.
  22. ↑ Buitenhuis, Miranda; et al. (2007). "Molecular mechanisms underlying FIP1L1-PDGFRA-mediated myeloproliferation". Cancer Research. 67 (8): 3759–3766. doi:10.1158/0008-5472.CAN-06-4183. ISSN 0008-5472. PMID 17440089.
  23. ↑ Rosemarin, A, and Feldweg, A. Hypereosinophilic syndromes: Treatement. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA. April 2020


Notes

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*Citation of this Page: “Myeloid/lymphoid neoplasm with PDGFRA rearrangement”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/11/2025, https://ccga.io/index.php/HAEM5:Myeloid/lymphoid_neoplasm_with_PDGFRA_rearrangement.

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