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HAEM5:Myeloid/lymphoid neoplasm with JAK2 rearrangement (view source)
Revision as of 12:42, 24 March 2025
, 24 Marchno edit summary
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__TOC__
−==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.}}</blockquote>
−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 class="blockedit">
−<center><span style="color:Maroon">'''End of V4 Section'''</span>
−----
−</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.}}</blockquote>
−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 class="blockedit">
−<center><span style="color:Maroon">'''End of V4 Section'''</span>
−----
−</blockquote>
'''+
{{Under Construction}}
{{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 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>
}}</blockquote>
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Jessica Snider, M.D. and Daynna J. Wolff, PhD
Jessica Snider, M.D. and Daynna J. Wolff, PhD
−==WHO Classification of Disease==
==WHO Classification of Disease==
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−==WHO Essential and Desirable Genetic Diagnostic Criteria==
==WHO Essential and Desirable Genetic Diagnostic Criteria==
<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
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−<blockquote class='blockedit'>{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}</blockquote>
+<blockquote class="blockedit">{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}</blockquote>
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{| class="wikitable sortable"
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−<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
+<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)
* Chromosomal Rearrangements (Gene Fusions)
* Individual Region Genomic Gain/Loss/LOH
* Individual Region Genomic Gain/Loss/LOH
* Characteristic Chromosomal Patterns
* Characteristic Chromosomal Patterns
* Gene Mutations (SNV/INDEL)}}</blockquote>
* Gene Mutations (SNV/INDEL)}}</blockquote>
−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.
+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">{{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>. 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>
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>
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−<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote>
+<blockquote class="blockedit">{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote>
There are no known recurrent genomic loss/gain or LOH pattern associated with entity.
There are no known recurrent genomic loss/gain or LOH pattern associated with entity.
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+<blockquote class="blockedit">{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}</blockquote>
There are no known secondary chromosomal changes and no pattern of other chromosome aberrations.
There are no known secondary chromosomal changes and no pattern of other chromosome aberrations.
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|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], 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.}}</blockquote>
+<blockquote class="blockedit">{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}</blockquote>
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" />
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" />
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−<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>
+<blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>
''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>
''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>
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''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>
''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" />
+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">{{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>
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−<br />
==Notes==
==Notes==
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<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>.
<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]]
+[[Category:HAEM5]]
+[[Category:DISEASE]]
+[[Category:Diseases M]]