Bailey.Glen at 21:23, 4 December 2023

2023-12-04T21:23:06Z

← Older revision		Revision as of 16:23, 4 December 2023
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	==Links==		==Links==

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

	[[PCM1]]		[[PCM1]]

Bailey.Glen at 18:41, 3 November 2023

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 ==Primary Author(s)*==
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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.

Bailey.Glen: Created page with "==Primary Author(s)*== Jessica Snider, M.D. and Daynna J. Wolff, PhD TOC ==Cancer Category/Type== Acute Myeloid Leukemia/Myeloid/lymphoid neoplasm with eosinophilia =..."

2023-11-03T18:01:12Z

Created page with "==Primary Author(s)*== Jessica Snider, M.D. and Daynna J. Wolff, PhD __TOC__ ==Cancer Category/Type== Acute Myeloid Leukemia/Myeloid/lymphoid neoplasm with eosinophilia =..."

New page

==Primary Author(s)*==

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

__TOC__

==Cancer Category/Type==

Acute Myeloid Leukemia/Myeloid/lymphoid neoplasm with eosinophilia

==Cancer Sub-Classification / Subtype==

''PCM1/JAK2''-Mediated myeloid/lymphoid neoplasm with eosinophilia

==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==

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" /> 

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" />

==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==

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" />.

==Chromosomal Rearrangements (Gene Fusions)==

{| 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
|}

==Characteristic Chromosomal Aberrations / Patterns==

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

==Genomic Gain/Loss/LOH==

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

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===
==Epigenomics (Methylation)==

There are no known epigenomic modifiers.

==Genes and Main Pathways Involved==

''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.5

''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.6

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" />

==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.

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
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 course1. 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.2

==Familial Forms==

No familial forms have been documented.

==Other Information==

==Links==

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

[[PCM1]]

[[JAK2]]

==References==
<references />

==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.

HAEM4:Myeloid/Lymphoid Neoplasms with PCM1-JAK2 - Revision history

Bailey.Glen at 21:23, 4 December 2023

Bailey.Glen at 18:41, 3 November 2023

Bailey.Glen: Created page with "==Primary Author(s)*== Jessica Snider, M.D. and Daynna J. Wolff, PhD __TOC__ ==Cancer Category/Type== Acute Myeloid Leukemia/Myeloid/lymphoid neoplasm with eosinophilia =..."

Bailey.Glen: Created page with "==Primary Author(s)*== Jessica Snider, M.D. and Daynna J. Wolff, PhD TOC ==Cancer Category/Type== Acute Myeloid Leukemia/Myeloid/lymphoid neoplasm with eosinophilia =..."