View source for HAEM5:Myeloid/lymphoid neoplasm with JAK2 rearrangement

{{DISPLAYTITLE:Myeloid/lymphoid neoplasm with JAK2 rearrangement}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]

{{Under Construction}}

<blockquote class='blockedit'>{{Box-round|title=Content 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 PCM1-JAK2]].
}}</blockquote>

<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ 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 to a table, click within the table and select the > symbol that appears to be given options. 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 </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>

==Primary Author(s)*==

Jessica Snider, M.D. and Daynna J. Wolff, PhD

__TOC__

==WHO Classification of Disease==

{| class="wikitable"
!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 JAK2 rearrangement
|}

==Definition / Description of Disease==

A hematologic neoplasm comprised of pluripotent (lymphoid-myeloid) stem cells characteristically seen with eosinophilia that result from the formation of a fusion between the ''PCM1'' and ''JAK2'' genes, leading to the expression of an aberrant tyrosine kinase. Due to its pluripotent nature, the hematologic stem cells can give rise to eosinophils, neutrophils, B-lymphoid and T-lymphoid cells. The presence of eosinophilia is not required for the diagnosis.<ref name=":0">Bain BJ, Horny HP, Arber DA, et al. Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of ''PDGFRA'', ''PDGFRB'' or ''FGFR1'', or with ''PCM1-JAK2''., 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, p129-171.</ref><ref>{{Cite journal|last=Reiter|first=Andreas|last2=Gotlib|first2=Jason|date=2017|title=Myeloid neoplasms with eosinophilia|url=https://ashpublications.org/blood/article/129/6/704/36333/Myeloid-neoplasms-with-eosinophilia|journal=Blood|language=en|volume=129|issue=6|pages=704–714|doi=10.1182/blood-2016-10-695973|issn=0006-4971}}</ref><ref>{{Cite journal|last=Baer|first=Constance|last2=Muehlbacher|first2=Verena|last3=Kern|first3=Wolfgang|last4=Haferlach|first4=Claudia|last5=Haferlach|first5=Torsten|date=2018|title=Molecular genetic characterization of myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2|url=http://www.haematologica.org/lookup/doi/10.3324/haematol.2017.187302|journal=Haematologica|language=en|volume=103|issue=8|pages=e348–e350|doi=10.3324/haematol.2017.187302|issn=0390-6078|pmc=PMC6068021|pmid=29567772}}</ref>

==Synonyms / Terminology==

Chronic eosinophilic leukemia with ''PCM1/JAK2''

''PCM1/JAK2'' –associated chronic eosinophilic leukemia

Myeloid and lymphoid neoplasms associated with JAK2 rearrangement

JAK2-associated Hypereosinophilic syndrome

Myeloid and lymphoid neoplasms with JAK2 rearrangement

Myeloproliferative variant of the hypereosinophilic syndrome
==Epidemiology / Prevalence==

This disease is rare; the incidence of hypereosinophilia in general is only 0.036 per 100,000 and genetic causes represent only a small portion of these<ref>{{Cite journal|last=Crane|first=Martin M.|last2=Chang|first2=Cindy Ma|last3=Kobayashi|first3=Monica G.|last4=Weller|first4=Peter F.|date=2010|title=Incidence of myeloproliferative hypereosinophilic syndrome in the United States and an estimate of all hypereosinophilic syndrome incidence|url=https://linkinghub.elsevier.com/retrieve/pii/S0091674910005816|journal=Journal of Allergy and Clinical Immunology|language=en|volume=126|issue=1|pages=179–181|doi=10.1016/j.jaci.2010.03.035|pmc=PMC5781228|pmid=20639012}}</ref>There is a significant male predominance with a median age of 47 years old (age range 7-77)<ref name=":0" />  As of August 2018, only 40 cases had been reported<ref name=":2">{{Cite journal|last=Tang|first=Guilin|last2=Sydney Sir Philip|first2=John Kennedy|last3=Weinberg|first3=Olga|last4=Tam|first4=Wayne|last5=Sadigh|first5=Sam|last6=Lake|first6=Jonathan I.|last7=Margolskee|first7=Elizabeth M.|last8=Rogers|first8=Heesun J.|last9=Miranda|first9=Roberto N.|date=2019|title=Hematopoietic neoplasms with 9p24/JAK2 rearrangement: a multicenter study|url=http://www.nature.com/articles/s41379-018-0165-9|journal=Modern Pathology|language=en|volume=32|issue=4|pages=490–498|doi=10.1038/s41379-018-0165-9|issn=0893-3952}}</ref>

==Clinical Features==

Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>
{| class="wikitable"
|'''Signs and Symptoms'''
|<span class="blue-text">EXAMPLE:</span> Asymptomatic (incidental finding on complete blood counts)

<span class="blue-text">EXAMPLE:</span> B-symptoms (weight loss, fever, night sweats)

<span class="blue-text">EXAMPLE:</span> Fatigue

<span class="blue-text">EXAMPLE:</span> Lymphadenopathy (uncommon)
|-
|'''Laboratory Findings'''
|<span class="blue-text">EXAMPLE:</span> Cytopenias

<span class="blue-text">EXAMPLE:</span> Lymphocytosis (low level)
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}

Patients typically present with features of a myeloproliferative disorder or MDS/MPN and most have eosinophilia and/or bone marrow  fibrosis<ref name=":2" /><ref name=":1">{{Cite journal|last=Hoeller|first=Sylvia|last2=Walz|first2=Christoph|last3=Reiter|first3=Andreas|last4=Dirnhofer|first4=Stephan|last5=Tzankov|first5=Alexandar|date=2011|title=PCM1–JAK2-fusion: a potential treatment target in myelodysplastic–myeloproliferative and other hemato-lymphoid neoplasms|url=http://www.tandfonline.com/doi/full/10.1517/14728222.2011.538683|journal=Expert Opinion on Therapeutic Targets|language=en|volume=15|issue=1|pages=53–62|doi=10.1517/14728222.2011.538683|issn=1472-8222}}</ref>. Patients in chronic phase tend to progress to AML quickly; some present with de novo acute leukemia, either myeloid or lymphoid<ref name=":1" /><ref name=":2" /><sup> </sup>

In general, patients with this disorder have weakness/fatigue (~26%), cough (~24%), myaligias/angioedema (~14%), rash or fever (~12%) and rhinitis (~10%)<ref>{{Cite journal|last=Gotlib|first=Jason|date=2017|title=World Health Organization-defined eosinophilic disorders: 2017 update on diagnosis, risk stratification, and management|url=http://doi.wiley.com/10.1002/ajh.24880|journal=American Journal of Hematology|language=en|volume=92|issue=11|pages=1243–1259|doi=10.1002/ajh.24880}}</ref> ; lymphadenopathy and splenomegaly are common<ref name=":2" /> 

</blockquote>
==Sites of Involvement==

Peripheral blood and bone marrow

==Morphologic Features==

Patients often have a hypercellular bone marrow with increased eosinophils and fibrosis<ref name=":0" /><ref name=":2" />.Increased granuolpoiesis with eosinophilia and neutrophil precursors, including myeloblasts<ref name=":0" /><ref name=":2" />. Dyserythropoiesis and dysgranulopoiesis are not typical but may be observed<ref name=":0" /><ref name=":2" />  Increased lymphoblasts may also be seen with blast cells having high nuclear to cytoplasmic ratios and open chromatin. If eosinophilia is present, it is comprised mainly of mature eosinophils with scattered immature forms. Eosinophilic abnormalities can be seen and include sparse granulation with small forms, vacuoles in the cytoplasm, increased eosinophil size, and nuclear hypo- and hypersegmentation. 

==Immunophenotype==

Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||<span class="blue-text">EXAMPLE:</span> CD1
|-
|Positive (subset)||<span class="blue-text">EXAMPLE:</span> CD2
|-
|Negative (universal)||<span class="blue-text">EXAMPLE:</span> CD3
|-
|Negative (subset)||<span class="blue-text">EXAMPLE:</span> CD4
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Immunophenotype|The content below was from the old template. Please incorporate above.}}

IHC can be used to characterize acute myeloid transformation and myeloblasts express dim CD45, dim CD34, dim CD117, HLA-DR, dim CD33, and dim CD13<ref name=":0" />. In addition, For the cases with lymphoid components, IHC can assist with assessment and show dim CD19 and dim CD10, consistent with lymphoblast lineage<ref name=":0" /><ref name=":2" />.

</blockquote>
==Chromosomal Rearrangements (Gene Fusions)==

Put your text here and fill in the table

{| class="wikitable sortable"
|-
!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
|-
|<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)||<span class="blue-text">EXAMPLE:</span> 3'ABL1 / 5'BCR||<span class="blue-text">EXAMPLE:</span> der(22)||<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
<span class="blue-text">EXAMPLE:</span> 30% (add reference)
|Yes
|No
|Yes
|<span class="blue-text">EXAMPLE:</span>

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).
|}		
			

<blockquote class='blockedit'>{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}

{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|-
|         t(8;9)(p22;p24.1)||3'JAK2 / 5'PCM1
|der(8)||rare
|}		
			
</blockquote>


<blockquote class='blockedit'>{{Box-round|title=v4: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)}}
Most patients present with MPN with variable degrees of eosinophilia in blood and/or bone marrow, frequent marrow fibrosis, and large aggregates of immature erythroid precursors, and clinically exhibit hepatosplenomegagly and lymphadenopathy<ref name=":2" />. However, diagnosis may be difficult in cases without obvious eosinophilia. 

Due to the variations in presentation, the prognosis is mainly dependent on the phase at presentation, but generally tends to have an aggressive course<sup>1</sup>. There currently are no approved therapies for ''PCM1/JAK2''-mediated myeloid/lymphoid neoplasm with eosinophilia; however, ''JAK2'' inhibitors have been approved for other hematopoietic neoplasms with constitutively activated ''JAK2'' kinases.<sup>2</sup>

</blockquote>
==Individual Region Genomic Gain / Loss / LOH==

Put your text here and fill in the table <span style="color:#0070C0">(''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. Do not delete table.'') </span>

{| class="wikitable sortable"
|-
!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
|-
|<span class="blue-text">EXAMPLE:</span>

7
|<span class="blue-text">EXAMPLE:</span> Loss
|<span class="blue-text">EXAMPLE:</span>

chr7:1- 159,335,973 [hg38]
|<span class="blue-text">EXAMPLE:</span>

chr7
|Yes
|Yes
|No
|<span class="blue-text">EXAMPLE:</span>

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).
|-
|<span class="blue-text">EXAMPLE:</span>

8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>

chr8:1-145,138,636 [hg38]
|<span class="blue-text">EXAMPLE:</span>

chr8
|No
|No
|No
|<span class="blue-text">EXAMPLE:</span>

Common recurrent secondary finding for t(8;21) (add reference).
|}

<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}

There are no known recurrent genomic loss/gain or LOH pattern associated with entity.
</blockquote>
==Characteristic Chromosomal Patterns==

Put your text here <span style="color:#0070C0">(''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. Do not delete table.'')</span>

{| class="wikitable sortable"
|-
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|<span class="blue-text">EXAMPLE:</span>

Co-deletion of 1p and 18q
|Yes
|No
|No
|<span class="blue-text">EXAMPLE:</span>

See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|}

<blockquote class='blockedit'>{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}

There are no known secondary chromosomal changes and no pattern of other chromosome aberrations.  

</blockquote>
==Gene Mutations (SNV / INDEL)==

Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well as 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. Do not delete table.'') </span>

{| class="wikitable sortable"
|-
!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
|-
|<span class="blue-text">EXAMPLE:</span> TP53; Variable LOF mutations

<span class="blue-text">EXAMPLE:</span>

EGFR; Exon 20 mutations

<span class="blue-text">EXAMPLE:</span> BRAF; Activating mutations
|<span class="blue-text">EXAMPLE:</span> TSG
|<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)

<span class="blue-text">EXAMPLE:</span> 30% (add Reference)
|<span class="blue-text">EXAMPLE:</span> IDH1 R123H
|<span class="blue-text">EXAMPLE:</span> EGFR amplification
|
|
|
|<span class="blue-text">EXAMPLE:</span>  Excludes hairy cell leukemia (HCL) (add reference).
<br />
|}
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.


<blockquote class='blockedit'>{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}

Given the rarity of the entity, there are no known recurrent aberrations. For the largest series studied, most cases were negative for mutations. However, some cases showed variants in genes associated with myeloid malignancies (ASXL1, RUNX1, SRSF2, TET2, BCOR) and one patient with B-ALL transformation showed variants in ETV6 and TP53<ref name=":2" />
===Other Mutations===
</blockquote>
==Epigenomic Alterations==

There are no known epigenomic modifiers. 

==Genes and Main Pathways Involved==

Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table. Do not delete table.'')</span>
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|<span class="blue-text">EXAMPLE:</span> BRAF and MAP2K1; Activating mutations
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|-
|<span class="blue-text">EXAMPLE:</span> CDKN2A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|-
|<span class="blue-text">EXAMPLE:</span>  KMT2C and ARID1A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span>  Histone modification, chromatin remodeling
|<span class="blue-text">EXAMPLE:</span>  Abnormal gene expression program
|}

<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}

''PCM1'' (pericentriolar material 1) is a protein present in cytoplasmic granules and can be found in association with the centrosome. ''PCM1'' is indirectly responsible for microtubule anchoring, which is necessary for a variety of cellular functions, including intracellular transport and cell division. The gene is located at band 8p22 and includes 41 exons.<sup>5</sup>

''JAK2'' (janus kinase 2) is a tyrosine kinase responsible for activation of the ''JAK-STAT'' pathway by mediating tyrosine phosphorylation, leading to cell proliferation and differentiation. Constitutive activation of ''JAK2'' can result from chromosomal translocations and lead to uncontrolled proliferation of hematopoietic cells. The gene is located at band 9p24.1 and includes 25 exons.<sup>6</sup>

The PCM1-JAK2 fusion product retains the coiled-coil domains of ''PCM1'' and the activating tyrosine kinase domain of ''JAK2''. Thus PCM1-JAK2 fusion produces an aberrant tyrosine kinase that results in constitutive activation of the JAK2–STAT pathway<ref name=":1" />

</blockquote>
==Genetic Diagnostic Testing Methods==

Diagnosis of this entity is made when a chromosome analysis showing a t(8;9) correlates with the clinical and morphological phenotype of the patient and/or when the fusion is confirmed by ancillary testing. FISH with a dual color, dual fusion probe for PCM1-JAK2 and sequencing of RNA to detect the functional fusion are the most commonly used methods to confirm this diagnosis. FISH with a JAK2 break-apart probe may also provide useful information to confirm a diagnosis.   

However, because the clinical presentation can vary and this disease can show many overlapping morphological features of other entities, the PCM1-JAK2 fusion or 8;9 translocation may be detected without overt suspicion. Therefore, agnostic genomic methods such as large panels of RNA fusions known to be associated with myeloid or lymphoid malignancies, whole exome/genome sequencing and occasionally chromosomal microarray analysis may provide evidence for this diagnosis. 

==Familial Forms==

No familial forms have been documented.

==Additional Information==

==Links==

[[HAEM4:Myeloid/Lymphoid Neoplasms with Eosinophilia and Rearrangement of PDGFRA, PDGFRB or FGFR1, or with PCM1-JAK2]]

[[PCM1]]

[[JAK2]]

==References==
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'''

==Notes==
<nowiki>*</nowiki>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.
<nowiki>*</nowiki>''Citation of this Page'': “Myeloid/lymphoid neoplasm with JAK2 rearrangement”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Myeloid/lymphoid_neoplasm_with_JAK2_rearrangement</nowiki>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases M]]