View source for HAEM4:Myeloid/Lymphoid Neoplasms with ETV6-JAK2

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==Primary Author(s)*==

Lauren R. Crowson-Hindman, DO, MS and Daynna J. Wolff, PhD

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==Cancer Category/Type==

Acute myeloid leukemia/ myeloid/lymphoid neoplasms

==Cancer Sub-Classification / Subtype==

Myeloid/Lymphoid neoplasms with eosinophilia and gene rearrangement

==Definition / Description of Disease==

A rare myeloproliferative neoplasm comprised of pluripotent (lymphoid-myeloid) stem cells and variably associated with hypereosinophilic syndromes, with t(9;12)(p24.1;p13.2) resulting in fusion between ETV6 and JAK2 genes, leading to the expression of an aberrant tyrosine kinase<ref name=":0">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, p72-79.</ref><ref name=":1">{{Cite journal|last=Reiter|first=Andreas|last2=Gotlib|first2=Jason|date=2017-02-09|title=Myeloid neoplasms with eosinophilia|url=https://doi.org/10.1182/blood-2016-10-695973|journal=Blood|language=en|volume=129|issue=6|pages=704–714|doi=10.1182/blood-2016-10-695973|issn=0006-4971}}</ref>.

This entity is uncommon and not included as a formal entity in the WHO myeloid/lymphoid with eosinophilia classification<ref name=":0" />.

==Synonyms / Terminology==

Myeloid and lymphoid neoplasms associated with JAK2 rearrangement 

==Epidemiology / Prevalence==

This disease is rare with 8 cases reported in the 2017 WHO Classification and 12 reported by Cook et al<ref name=":0" /><ref name=":2">{{Cite journal|last=Cook|first=James R.|last2=Rogers|first2=Heesun J.|last3=Chandra|first3=Pranil K.|last4=Prescott|first4=James L.|last5=Mukherjee|first5=Sudipto|date=2020|title=Myeloid neoplasm with eosinophilia and ETV6-JAK2 fusion|url=https://www.tandfonline.com/doi/full/10.1080/10428194.2019.1658105|journal=Leukemia & Lymphoma|language=en|volume=61|issue=1|pages=213–216|doi=10.1080/10428194.2019.1658105|issn=1042-8194}}</ref>. The incidence of hypereosinophilia in general is only 0.036 per 100,000 and genetic causes represent only a small portion of these cases<ref>{{Cite journal|last=Crane|first=Martin M.|last2=Chang|first2=Cindy Ma|last3=Kobayashi|first3=Monica G.|last4=Weller|first4=Peter F.|date=2010-07|title=Incidence of myeloproliferative hypereosinophilic syndrome in the United States and an estimate of all hypereosinophilic syndrome incidence|url=https://doi.org/10.1016/j.jaci.2010.03.035|journal=Journal of Allergy and Clinical Immunology|volume=126|issue=1|pages=179–181|doi=10.1016/j.jaci.2010.03.035|issn=0091-6749|pmc=PMC5781228|pmid=20639012}}</ref>. 

==Clinical Features==

Myeloid and lymphoid malignancies associated with ETV6-JAK2 rearrangements include most commonly B-lymphoblastic leukemia (B-ALL) and T-lymphoblastic lymphoma/leukemia, and also MDS/MPN neoplasms and atypical chronic myeloid leukemia (CML)<ref name=":0" /><ref name=":2" />; see [https://doi.org/10.1080/10428194.2019.1658105 Table 1. Clinicopathologic details of prior cases reported to contain ETV6-JAK2 fusions]<ref name=":2" />. Cases of B-lymphoblastic leukemia/lymphoma may have features of BCR-ABL1-like lymphoblastic leukemia<ref name=":0" />. Patients rarely present with eosinophilia, and splenomegaly is a variable clinical finding<ref name=":0" /><ref name=":2" />.

==Sites of Involvement==

Peripheral blood and bone marrow

==Morphologic Features==

The small group of disorders is more heterogeneous than cases with PCM1-JAK2<ref name=":0" />. The BCR-JAK2 fusion causes a genetic alteration at the pluripotent lymphoid-myeloid stem cell stage, thus causing both myeloid and lymphoid neoplasms. Eosinophilia and neutrophil precursors may be present in the peripheral blood.  Patients often have hypercellular bone marrow with eosinophils and fibrosis; dyserythropoiesis and dysgranulopoiesis are uncommon but may occur. Monocytosis is uncommon<ref name=":0" />.

==Immunophenotype==

Immunophenotypic analysis may be useful in characterizing lymphoid components or monitoring for acute myeloid transformation<ref name=":0" />. 

==Chromosomal Rearrangements (Gene Fusions)==

Put your text here and/or fill in the table

{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Prevalence
|-
|t(9;12)(p24.1;p13.2)||ETV6-JAK2||Rare
|}		
			
==Characteristic Chromosomal Aberrations / Patterns==

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

==Genomic Gain/Loss/LOH==

There are no known recurrent genomic loss/gain or LOH patterns associated with this entity. 
==Gene Mutations (SNV/INDEL)==

There are no known recurrent aberrations. 

==Epigenomics (Methylation)==

There are no known epigenomic modifiers. 

==Genes and Main Pathways Involved==

Chromosomal translocations can lead to gene fusions such as ETV6–JAK2, BCR–JAK2, SSBP2–JAK2, PAX-5–JAK2, etc., that are associated with varying myeloid and lymphoid malignancies of aggressive nature<ref>{{Cite journal|last=Angelova|first=Svetlana|last2=Spassova|first2=Sylva|last3=Toshkov|first3=Stavri|last4=Shivarov|first4=Velizar|date=2011|title=Chromosomal translocation t(9;22)(p24;q11) appears to be recurrently associated with myeloid malignancy with aggressive course|url=http://www.tandfonline.com/doi/full/10.3109/10428194.2011.580025|journal=Leukemia & Lymphoma|language=en|volume=52|issue=9|pages=1809–1810|doi=10.3109/10428194.2011.580025|issn=1042-8194}}</ref>. 

JAK2 (janus kinase 2) is a tyrosine kinase responsible for the activation of the JAK-STAT pathway which mediates tyrosine phosphorylation, leading to cell differentiation and proliferation. Chromosomal translocations can lead to fusions that produce aberrant tyrosine kinase and result in constitutive activation of the JAK-STAT pathway. Both fusion proteins BCR-JAK2 and ETV6-JAK2 include the JH1 domain of JAK2, which is considered the catalytic domain and determines the activity potential of JAK2. The consequences of the aberrant JAK2 activation are neoplastic transformation and abnormal cell proliferation<ref>{{Cite journal|last=Xu|first=Yang|last2=Yin|first2=Jia|last3=Pan|first3=Jinlan|last4=Wu|first4=Chunxiao|last5=Wang|first5=Qinrong|last6=Yao|first6=Hong|last7=Wu|first7=Depei|last8=Chen|first8=Suning|last9=Sun|first9=Aining|date=2013|title=A BCR–JAK2 fusion gene from ins(22;9)(q11;p13p24) in a patient with atypical chronic myeloid leukemia|url=http://www.tandfonline.com/doi/full/10.3109/10428194.2012.762648|journal=Leukemia & Lymphoma|language=en|volume=54|issue=10|pages=2322–2324|doi=10.3109/10428194.2012.762648|issn=1042-8194}}</ref>. 

==Diagnostic Testing Methods==

Morphologic evaluation and flow cytometric immunophenotyping in conjunction with cytogenetic analysis, fluorescence in situ hybridization (FISH) and genetic testing are all required to identify molecular abnormalities in such variable clinical/hematologic presentations<ref name=":1" />. RT-PCR can identify in-frame transcripts of ETV6-JAK2 fusions, and FISH analyses of ''BCR/ABL1'', ''PDGFRA'', ''PDGFRB'', ''FGFR1'', ''JAK2'' gene regions can be used<ref name=":2" />. 

[https://ashpublications.org/view-large/figure/7559998/blood695973f1.jpeg Diagnostic algorithm] for hypereosinophilia, including eosinophilia-associated neoplasms<ref name=":1" />.

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

With this being such a rare entity, prognostic and therapeutic data is scarce. An aggressive disease course with variable sensitivity to current TK inhibitors has been reported<ref name=":1" />. Stem cell transplant may be the ultimate therapy of choice, with one case reported remaining disease-free for up over three years after transplant<ref>{{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>. 

==Familial Forms==

No familial forms have been documented. 

==Other Information==

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==Links==

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

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==References==
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<references />
===Notes===
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