Bailey.Glen: Created page with "{{Under Construction}} ==Primary Author(s)*== Lauren R. Crowson-Hindman, DO, MS and Daynna J. Wolff, PhD TOC ==Cancer Category/Type== Acute myeloid leukemia/ myeloid/l..."

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Created page with "{{Under Construction}} ==Primary Author(s)*== Lauren R. Crowson-Hindman, DO, MS and Daynna J. Wolff, PhD __TOC__ ==Cancer Category/Type== Acute myeloid leukemia/ myeloid/l..."

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{{Under Construction}}
==Primary Author(s)*==

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

__TOC__

==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;22)(p24.1;p11.2) resulting in fusion between BCR 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=Gotlib|first=Jason|last2=Reiter|first2=Andreas|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>.

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 11 cases reported in the 2017 WHO Classification and 15 reported by He et al<ref name=":0" /><ref name=":2">{{Cite journal|last=He|first=Rong|last2=Greipp|first2=Patricia T.|last3=Rangan|first3=Aruna|last4=Mai|first4=Ming|last5=Chen|first5=Dong|last6=Reichard|first6=Kaaren K.|last7=Nelsen|first7=Laura L.|last8=Pardanani|first8=Animesh|last9=Hanson|first9=Curtis A.|date=2016-05|title=BCR–JAK2 fusion in a myeloproliferative neoplasm with associated eosinophilia|url=https://doi.org/10.1016/j.cancergen.2016.03.002|journal=Cancer Genetics|volume=209|issue=5|pages=223–228|doi=10.1016/j.cancergen.2016.03.002|issn=2210-7762}}</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>. The median patient age is 51 years old with a slight male predominance, 2:1<ref name=":2" />.

==Clinical Features==

Myeloid and lymphoid malignancies associated with BCR-JAK2 rearrangements include myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) being the most common, as well as acute myeloid leukemia (AML), B-lymphoblastic leukemia (B-ALL) and rarely T-lymphoblastic lymphoma/leukemia; see [https://www.sciencedirect.com/science/article/pii/S2210776216300370#t0010 Table 1. Characteristics of reported myeloid and lymphoid neoplasms with ''BCR–JAK2'' fusions]<ref name=":2" />. Patients variably present with eosinophilia, and splenomegaly is a common clinical finding<ref name=":0" />.

The clinical course of JAK2-rearranged patients resembles other patients with leukemias associated with other tyrosine kinase fusion genes, such as BCR-ABL1 positive CML. However, the clinical course can be more aggressive, with patients in chronic phase disease quickly progressing to AML<ref name=":1" /><ref name=":3">{{Cite journal|last=Kantarcioglu|first=Bulent|last2=Kaygusuz-Atagunduz|first2=Isik|last3=Uzay|first3=Ant|last4=Toptas|first4=Tayfur|last5=Tuglular|first5=Tulin Firatli|last6=Bayik|first6=Mahmut|date=2015|title=Myelodysplastic syndrome with t(9;22)(p24;q11.2), a BCR-JAK2 fusion: case report and review of the literature|url=http://link.springer.com/10.1007/s12185-015-1792-2|journal=International Journal of Hematology|language=en|volume=102|issue=3|pages=383–387|doi=10.1007/s12185-015-1792-2|issn=0925-5710}}</ref>.

==Sites of Involvement==

Peripheral blood and bone marrow

==Morphologic Features==

This 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)==

{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Prevalence
|-
|t(9;22)(p24.1;p11.2)||BCR-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 BCR-JAK2 fusions, and FISH analyses of ''BCR/ABL1'', ''PDGFRA'', ''PDGFRB'', ''FGFR1'', ''JAK2'' gene regions can be used<ref name=":2" />.

It is also important to distinguish BCR-JAK2 from the classical BCR-ABL1 positive CML, as the former entity may be resistant to imatinib therapy<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)==

Most patients present with MDS/MPN neoplasms with a more aggressive clinical course and variable sensitivity to current tyrosine kinase (TK) inhibitors. With this being such a rare entity and such variable presentation, there is no precise treatment option for BCR-JAK2 fusion<ref name=":3" />. Survival is highly variable and can range from days to years<ref name=":0" />. Some cases demonstrate a promising initial clinical response to TK inhibitors, but this is short-lived and long-term disease-free survival may only be achieved by allogeneic hematopoietic stem cell transplantation (AHSCT). Thus, TK inhibitors may be limited in their therapeutic value as solely bridging therapy before stem cell transplant can be performed<ref name=":1" /><ref name=":2" />.

==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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HAEM4Backup:Myeloid/Lymphoid Neoplasms with BCR-JAK2 - Revision history

Bailey.Glen: Created page with "{{Under Construction}} ==Primary Author(s)*== Lauren R. Crowson-Hindman, DO, MS and Daynna J. Wolff, PhD __TOC__ ==Cancer Category/Type== Acute myeloid leukemia/ myeloid/l..."

Bailey.Glen: Created page with "{{Under Construction}} ==Primary Author(s)*== Lauren R. Crowson-Hindman, DO, MS and Daynna J. Wolff, PhD TOC ==Cancer Category/Type== Acute myeloid leukemia/ myeloid/l..."