Compendium of Cancer Genome Aberrations

HAEM5:B-lymphoblastic leukaemia/lymphoma with BCR::ABL1-like features: Difference between revisions

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==Primary Author(s)*==
==Primary Author(s)*==
Mark G. Evans, MD, Caris Life Sciences
Mark G. Evans, MD, Caris Life Sciences
Kilannin Krysiak, PhD, WashU Medicine


Sumire K. Kitahara, MD, Cedars-Sinai Medical Center
Sumire K. Kitahara, MD, Cedars-Sinai Medical Center
Line 51: Line 49:
==Gene Rearrangements==
==Gene Rearrangements==


B-lymphoblastic leukaemia/lymphoma with ''BCR::ABL1''-like features traditionally required diagnosis by gene expression (GEX) profiling<ref name=":1">{{Cite journal|last=Mullighan|first=Charles G.|last2=Su|first2=Xiaoping|last3=Zhang|first3=Jinghui|last4=Radtke|first4=Ina|last5=Phillips|first5=Letha A. A.|last6=Miller|first6=Christopher B.|last7=Ma|first7=Jing|last8=Liu|first8=Wei|last9=Cheng|first9=Cheng|date=2009|title=Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/19129520|journal=The New England Journal of Medicine|volume=360|issue=5|pages=470–480|doi=10.1056/NEJMoa0808253|issn=1533-4406|pmc=2674612|pmid=19129520}}</ref><ref name=":0">{{Cite journal|last=Den Boer|first=Monique L.|last2=van Slegtenhorst|first2=Marjon|last3=De Menezes|first3=Renée X.|last4=Cheok|first4=Meyling H.|last5=Buijs-Gladdines|first5=Jessica G. C. A. M.|last6=Peters|first6=Susan T. C. J. M.|last7=Van Zutven|first7=Laura J. C. M.|last8=Beverloo|first8=H. Berna|last9=Van der Spek|first9=Peter J.|date=2009|title=A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study|url=https://www.ncbi.nlm.nih.gov/pubmed/19138562|journal=The Lancet. Oncology|volume=10|issue=2|pages=125–134|doi=10.1016/S1470-2045(08)70339-5|issn=1474-5488|pmc=2707020|pmid=19138562}}</ref> and was found to exhibit a GEX profile similar to Philadelphia chromosome-positive B-lymphoblastic leukaemia/lymphoma but lacking ''BCR::ABL1''. The WHO<ref>WHO Classification of Tumours Editorial Board. Hematolymphoid tumors. Lyon (France): International Agency for Research on Cancer; 2022. [cited 2025 NOV 05]. (WHO classification of tumors series, 5th ed.). Available from: https:​//tumourclassification​.iarc.who.int.</ref> and ICC<ref>{{Cite journal|last=Campo|first=Elias|last2=Jaffe|first2=Elaine S.|last3=Cook|first3=James R.|last4=Quintanilla-Martinez|first4=Leticia|last5=Swerdlow|first5=Steven H.|last6=Anderson|first6=Kenneth C.|last7=Brousset|first7=Pierre|last8=Cerroni|first8=Lorenzo|last9=de Leval|first9=Laurence|date=2022-09-15|title=The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee|url=https://pubmed.ncbi.nlm.nih.gov/35653592|journal=Blood|volume=140|issue=11|pages=1229–1253|doi=10.1182/blood.2022015851|issn=1528-0020|pmc=9479027|pmid=35653592}}</ref> has since recognized recurring genomic alterations associated with the diagnosis of B-lymphoblastic leukaemia/lymphoma with ''BCR::ABL1''-like features, including  ABL-class rearrangements, JAK-STAT activating alterations, and others. Proper identification of this disease is important, as patients may respond to targeted therapies like tyrosine kinase inhibitors (TKIs)<ref name=":9" />; however, as most reports feature only single cases and limited series, consensus on the diagnostic/prognostic/therapeutic significance of the various genomic alterations has not been reached and is in the process of being established.   
B-lymphoblastic leukaemia/lymphoma with ''BCR::ABL1''-like features traditionally required diagnosis by gene expression (GEX) profiling<ref name=":1">{{Cite journal|last=Mullighan|first=Charles G.|last2=Su|first2=Xiaoping|last3=Zhang|first3=Jinghui|last4=Radtke|first4=Ina|last5=Phillips|first5=Letha A. A.|last6=Miller|first6=Christopher B.|last7=Ma|first7=Jing|last8=Liu|first8=Wei|last9=Cheng|first9=Cheng|date=2009|title=Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/19129520|journal=The New England Journal of Medicine|volume=360|issue=5|pages=470–480|doi=10.1056/NEJMoa0808253|issn=1533-4406|pmc=2674612|pmid=19129520}}</ref><ref name=":0">{{Cite journal|last=Den Boer|first=Monique L.|last2=van Slegtenhorst|first2=Marjon|last3=De Menezes|first3=Renée X.|last4=Cheok|first4=Meyling H.|last5=Buijs-Gladdines|first5=Jessica G. C. A. M.|last6=Peters|first6=Susan T. C. J. M.|last7=Van Zutven|first7=Laura J. C. M.|last8=Beverloo|first8=H. Berna|last9=Van der Spek|first9=Peter J.|date=2009|title=A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study|url=https://www.ncbi.nlm.nih.gov/pubmed/19138562|journal=The Lancet. Oncology|volume=10|issue=2|pages=125–134|doi=10.1016/S1470-2045(08)70339-5|issn=1474-5488|pmc=2707020|pmid=19138562}}</ref> and was found to exhibit a GEX profile similar to Philadelphia chromosome-positive B-lymphoblastic leukaemia/lymphoma but lacking ''BCR::ABL1''. The WHO<ref>WHO Classification of Tumours Editorial Board. Hematolymphoid tumors. Lyon (France): International Agency for Research on Cancer; 2022. [cited 2025 NOV 05]. (WHO classification of tumors series, 5th ed.). Available from: https:​//tumourclassification​.iarc.who.int.</ref> and ICC<ref>{{Cite journal|last=Campo|first=Elias|last2=Jaffe|first2=Elaine S.|last3=Cook|first3=James R.|last4=Quintanilla-Martinez|first4=Leticia|last5=Swerdlow|first5=Steven H.|last6=Anderson|first6=Kenneth C.|last7=Brousset|first7=Pierre|last8=Cerroni|first8=Lorenzo|last9=de Leval|first9=Laurence|date=2022-09-15|title=The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee|url=https://pubmed.ncbi.nlm.nih.gov/35653592|journal=Blood|volume=140|issue=11|pages=1229–1253|doi=10.1182/blood.2022015851|issn=1528-0020|pmc=9479027|pmid=35653592}}</ref> have since recognized recurring genomic alterations associated with B-lymphoblastic leukaemia/lymphoma with ''BCR::ABL1''-like features, including  ABL-class rearrangements, JAK-STAT activating alterations, and others. Proper identification of this disease is important, as patients may respond to targeted therapies like tyrosine kinase inhibitors (TKIs);<ref name=":9" /> however, as most reports feature only single cases and limited series, consensus on the diagnostic/prognostic/therapeutic significance of the various genomic alterations has not been reached and currently being established.   




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|'''Comment'''
|'''Comment'''
|-
|-
| rowspan="12" |'''''[[ABL1]]'''''
| rowspan="12" |''[[ABL1]]''
(9q34)
(9q34)
|''CENPC1''
|''CENPC1''
Line 150: Line 148:
|
|
|-
|-
| rowspan="3" |'''''[[ABL2]]'''''
| rowspan="3" |''[[ABL2]]''
(1q25.2)
(1q25.2)
|''PAG1''
|''PAG1''
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|
|
|-
|-
| rowspan="2" |'''''[[CRLF2]]'''''
| rowspan="2" |''[[CRLF2]]''
(Xp22.3 & Yp11.3)
(Xp22.3 & Yp11.3)
|''[[IGH]]''
|''[[IGH]]''
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|
|
|-
|-
| rowspan="3" |'''''CSF1R'''''
| rowspan="3" |''CSF1R''
(5q32)
(5q32)
|''MEF2D''
|''MEF2D''
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|
|
|-
|-
|'''''DGKH''''' (13q14.1)
|''DGKH'' (13q14.1)
|''ZFAND3''
|''ZFAND3''
|t(6;13)(p21.2;q14.1)
|t(6;13)(p21.2;q14.1)
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|Requires complex rearrangement due to incompatible orientation of genes with respect to chromosome arms
|Requires complex rearrangement due to incompatible orientation of genes with respect to chromosome arms
|-
|-
| rowspan="4" |'''''EPOR''''' (19p13.2)
| rowspan="4" |''EPOR'' (19p13.2)
|''[[IGH]]''
|''[[IGH]]''
|ins(14;19)(q32;p13.2p13.2)
|ins(14;19)(q32;p13.2p13.2)
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|
|
|-
|-
|'''''IL2RB''''' (22q12.3)
|''IL2RB'' (22q12.3)
|''MYH9''
|''MYH9''
|22q12.3 rearrangement
|22q12.3 rearrangement
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|On the same chromosome arm; however, a simple deletion cannot cause the fusion due to the orientation of genes
|On the same chromosome arm; however, a simple deletion cannot cause the fusion due to the orientation of genes
|-
|-
| rowspan="22" |'''''[[JAK2]]'''''
| rowspan="22" |''[[JAK2]]''
(9p24.1)
(9p24.1)
|''ATF7IP''
|''ATF7IP''
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|
|
|-
|-
|'''''[[PDGFRA]]'''''
|''[[PDGFRA]]''
(4q12)
(4q12)
|''FIP1L1''
|''FIP1L1''
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|Interstitial deletion. Seen also in myeloid/lymphoid neoplasms with eosinophilia
|Interstitial deletion. Seen also in myeloid/lymphoid neoplasms with eosinophilia
|-
|-
| rowspan="8" |'''''[[PDGFRB]]''''' (5q32)
| rowspan="8" |''[[PDGFRB]]'' (5q32)
|''ATF7IP''
|''ATF7IP''
|t(5;12)(q32;p13.1)
|t(5;12)(q32;p13.1)
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|
|
|-
|-
| rowspan="3" |'''''PTK2B''''' (8p21.2)
| rowspan="3" |''PTK2B'' (8p21.2)
|''[[KDM6A]]''
|''[[KDM6A]]''
|t(X;8)(p11.3;p21.2)
|t(X;8)(p11.3;p21.2)
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|
|
|-
|-
| rowspan="3" |'''''TYK2''''' (19p13.2)
| rowspan="3" |''TYK2'' (19p13.2)
|''MYB''
|''MYB''
|t(6;19)(q23.3;p13.2)
|t(6;19)(q23.3;p13.2)
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|P
|P
|Yes, [https://www.nccn.org/professionals/physician_gls/pdf/all.pdf NCCN - Acute Lymphoblastic leukaemia]
|Yes, [https://www.nccn.org/professionals/physician_gls/pdf/all.pdf NCCN - Acute Lymphoblastic leukaemia]
|Monoallelic (often partial) deletion of the IKAROS transcription factor, encoded by ''IKZF1'', is one of the most frequently observed genetic abnormalities in B-lymphoblastic leukaemia/lymphoma with ''BCR::ABL1''-like features, although this finding is not specific and not included in the definition<ref name=":3">{{Cite journal|last=Boer|first=Judith M.|last2=Marchante|first2=João R. M.|last3=Evans|first3=William E.|last4=Horstmann|first4=Martin A.|last5=Escherich|first5=Gabriele|last6=Pieters|first6=Rob|last7=Den Boer|first7=Monique L.|date=2015|title=BCR-ABL1-like cases in pediatric acute lymphoblastic leukemia: a comparison between DCOG/Erasmus MC and COG/St. Jude signatures|url=https://www.ncbi.nlm.nih.gov/pubmed/26045294|journal=Haematologica|volume=100|issue=9|pages=e354–357|doi=10.3324/haematol.2015.124941|issn=1592-8721|pmc=4800707|pmid=26045294}}</ref>; ''IKZF1'' deletion is associated with poor prognosis.<ref>{{Cite journal|last=van der Veer|first=Arian|last2=Waanders|first2=Esmé|last3=Pieters|first3=Rob|last4=Willemse|first4=Marieke E.|last5=Van Reijmersdal|first5=Simon V.|last6=Russell|first6=Lisa J.|last7=Harrison|first7=Christine J.|last8=Evans|first8=William E.|last9=van der Velden|first9=Vincent H. J.|date=2013-10-10|title=Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL|url=https://pubmed.ncbi.nlm.nih.gov/23974192|journal=Blood|volume=122|issue=15|pages=2622–2629|doi=10.1182/blood-2012-10-462358|issn=1528-0020|pmc=3795461|pmid=23974192}}</ref>
|Monoallelic (often partial) deletion of the IKAROS transcription factor, encoded by ''IKZF1'', is one of the most frequently observed genetic abnormalities in B-lymphoblastic leukaemia/lymphoma with ''BCR::ABL1''-like features, although this finding is not specific and not included in the definition;<ref name=":3">{{Cite journal|last=Boer|first=Judith M.|last2=Marchante|first2=João R. M.|last3=Evans|first3=William E.|last4=Horstmann|first4=Martin A.|last5=Escherich|first5=Gabriele|last6=Pieters|first6=Rob|last7=Den Boer|first7=Monique L.|date=2015|title=BCR-ABL1-like cases in pediatric acute lymphoblastic leukemia: a comparison between DCOG/Erasmus MC and COG/St. Jude signatures|url=https://www.ncbi.nlm.nih.gov/pubmed/26045294|journal=Haematologica|volume=100|issue=9|pages=e354–357|doi=10.3324/haematol.2015.124941|issn=1592-8721|pmc=4800707|pmid=26045294}}</ref> ''IKZF1'' deletion is associated with poor prognosis.<ref>{{Cite journal|last=van der Veer|first=Arian|last2=Waanders|first2=Esmé|last3=Pieters|first3=Rob|last4=Willemse|first4=Marieke E.|last5=Van Reijmersdal|first5=Simon V.|last6=Russell|first6=Lisa J.|last7=Harrison|first7=Christine J.|last8=Evans|first8=William E.|last9=van der Velden|first9=Vincent H. J.|date=2013-10-10|title=Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL|url=https://pubmed.ncbi.nlm.nih.gov/23974192|journal=Blood|volume=122|issue=15|pages=2622–2629|doi=10.1182/blood-2012-10-462358|issn=1528-0020|pmc=3795461|pmid=23974192}}</ref>
|-
|-
|9
|9
|Loss
|Loss
|chr9:21,967,752-21,995,324/
|chr9:21,967,752-21,995,324
chr9:22,002,903-22,009,313
chr9:22,002,903-22,009,313


[GRCh38/hg38]
[GRCh38/hg38]
|''CDKN2A/B''
|''CDKN2A''
''CDKN2B''
|Unknown
|Unknown
|No
|No
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|Chromosome X/Y cryptic deletion or translocation
Co-deletion of 1p and 18q
|These changes cause ''CRLF2'' overexpression, upregulating the JAK-STAT pathway.
|<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).
|Common (>20%)
|Common (Oligodendroglioma)
|P
|Unknown
|No
|
|Chromosome X/Y abnormalities include either translocation of the immunoglobin heavy chain enhance locus into ''CRLF2'' (''IGH''::''CRLF2''—more commonly seen in adults) or a cryptic deletion involving the PAR1 psuedoautosomal region, resulting in fusion of ''CRLF2'' and ''P2RY8'' (more commonly seen in children); these alterations involving ''CRLF2'' have been associated with poor survival;<ref name=":7">{{Cite journal|last=Konoplev|first=Sergej|last2=Lu|first2=Xinyan|last3=Konopleva|first3=Marina|last4=Jain|first4=Nitin|last5=Ouyang|first5=Juan|last6=Goswami|first6=Maitrayee|last7=Roberts|first7=Kathryn G.|last8=Valentine|first8=Marc|last9=Mullighan|first9=Charles G.|date=2017|title=CRLF2-Positive B-Cell Acute Lymphoblastic Leukemia in Adult Patients: A Single-Institution Experience|url=https://www.ncbi.nlm.nih.gov/pubmed/28340183|journal=American Journal of Clinical Pathology|volume=147|issue=4|pages=357–363|doi=10.1093/ajcp/aqx005|issn=1943-7722|pmid=28340183}}</ref> very rare alternative translocations involving ''CRLF2'' have also been observed.
|
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|Polysomy or iAMP21
Microsatellite instability - hypermutated
|These changes stem from telomere attrition that results in amplification of all or a region of chromosome 21.
|
|Rare (<5%)
|Rare (<5%)
|<span class="blue-text">EXAMPLE:</span> P, T
|P
|
|No
|
|iAMP21 is considered high-risk cytogenetic abnormality/poor prognostic indicator, but it is not specific to B-lymphoblastic leukaemia/lymphoma with ''BCR::ABL1''-like features and can be seen in other B-lymphoblastic leukaemia/lymphomas.<ref>{{Cite journal|last=Koleilat|first=Alaa|last2=Smadbeck|first2=James B.|last3=Zepeda-Mendoza|first3=Cinthya J.|last4=Williamson|first4=Cynthia M.|last5=Pitel|first5=Beth A.|last6=Golden|first6=Crystal L.|last7=Xu|first7=Xinjie|last8=Greipp|first8=Patricia T.|last9=Ketterling|first9=Rhett P.|date=2022-12|title=Characterization of unusual iAMP21 B-lymphoblastic leukemia (iAMP21-ALL) from the Mayo Clinic and Children's Oncology Group|url=https://pubmed.ncbi.nlm.nih.gov/35771717|journal=Genes, Chromosomes & Cancer|volume=61|issue=12|pages=710–719|doi=10.1002/gcc.23084|issn=1098-2264|pmc=9549522|pmid=35771717}}</ref>
|-
|
|
|
|
|
|
|}
|}


<blockquote class="blockedit">{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}</blockquote>
 
Approximately half of cases demonstrate rearrangements resulting in overexpression of CRLF2<ref name=":7">{{Cite journal|last=Konoplev|first=Sergej|last2=Lu|first2=Xinyan|last3=Konopleva|first3=Marina|last4=Jain|first4=Nitin|last5=Ouyang|first5=Juan|last6=Goswami|first6=Maitrayee|last7=Roberts|first7=Kathryn G.|last8=Valentine|first8=Marc|last9=Mullighan|first9=Charles G.|date=2017|title=CRLF2-Positive B-Cell Acute Lymphoblastic Leukemia in Adult Patients: A Single-Institution Experience|url=https://www.ncbi.nlm.nih.gov/pubmed/28340183|journal=American Journal of Clinical Pathology|volume=147|issue=4|pages=357–363|doi=10.1093/ajcp/aqx005|issn=1943-7722|pmid=28340183}}</ref>. These rearrangements are the result of either translocation of immunoglobin heavy chain enhance locus into ''CRLF2'' (''IGH''-''CRLF2''—more commonly seen in adults) or through a cryptic deletion on chromosome X/Y involving the PAR1 psuedoautosomal region, resulting in fusion of ''CRLF2'' to ''P2RY8'' (more commonly seen in children). Very rare alternative translocations involving ''CRLF2'' have also been observed.
[Abnormal fluorescence ''in situ'' hybridization (FISH) results in interphase nuclei from a bone marrow sample using the ''CRLF2'' dual-color, break-apart (Cytocell) and ''IGH'' dual-color, break-apart probes, reflective of ''IGH''::''CRLF2'' rearrangement]
[[File:FISH 1.jpg|thumb|none]]
[[File:FISH 1.jpg|thumb|none]]


[[File:FISH 2.jpg|thumb|none|link=Special:FilePath/FISH_2.jpg]]
[[File:FISH 2.jpg|thumb|none|link=Special:FilePath/FISH_2.jpg]]


[Abnormal FISH results in interphase nuclei from a bone marrow sample using the ''CRLF2'' dual-color, break-apart (Cytocell) and ''IGH'' dual-color, break-apart probes, reflective of ''IGH''-''CRLF2'' fusion]
 
[Concurrent abnormal karyotype with trisomy 21 and a translocation involving chromosomes X, 14, and 2 in 9 of 13 cells available for analysis; metaphase FISH with the ''IGH'' break-apart probe (Vysis) confirms the presence of 5’ ''IGH'' (green signal) on the abnormal chromosome Xp33.1 (''CRLF2'' locus), highly suggestive on an ''IGH''::''CRLF2'' fusion rearrangement: 47,XX,+21c[4]/47,idem,der(X)t(X;14)(p33.1;q32),der(2)t(2;14)(p11.2;q11.2)t(X;14),der(14)t(2;14)[5]/46,XX[4].ish der(X)(5’IGH+),der(2)(3’IGH+)]
 
[[File:FISH 3.jpg|thumb|none]]
[[File:FISH 3.jpg|thumb|none]]


[[File:Karyotype.jpg|thumb|none]]
[[File:Karyotype.jpg|thumb|none]]
[Concurrent abnormal karyotype with trisomy 21 and a translocation involving chromosomes X, 14, and 2 in 9 of 13 cells available for analysis. Metaphase FISH with the ''IGH'' break-apart probe (Vysis) confirms the presence of 5’ ''IGH'' (green signal) on the abnormal chromosome Xp33.1 (''CRLF2'' locus), highly suggestive on an ''IGH''-''CRLF2'' fusion rearrangement.
47,XX,+21c[4]/47,idem,der(X)t(X;14)(p33.1;q32),der(2)t(2;14)(p11.2;q11.2)t(X;14),der(14)t(2;14)[5]/46,XX[4].ish der(X)(5’IGH+),der(2)(3’IGH+)]


(Images courtesy of Fabiola Quintero-Rivera, MD)
(Images courtesy of Fabiola Quintero-Rivera, MD)


<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==Gene Mutations (SNV/INDEL)==
==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 or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries 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. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.'') </span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
Line 669: Line 650:
!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|''CRLF2''
 
|[https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=128002578 p.F232C]
<br />
|Oncogene
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|Recurrent (5-20%)
|<span class="blue-text">EXAMPLE:</span> Oncogene
|Unknown
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|No
|<span class="blue-text">EXAMPLE:</span> T
|p.F232C is a gain-of-function mutation that results in constitutive dimerization and cytokine independent growth within the JAK-STAT pathway.<ref>{{Cite journal|last=Yoda|first=Akinori|last2=Yoda|first2=Yuka|last3=Chiaretti|first3=Sabina|last4=Bar-Natan|first4=Michal|last5=Mani|first5=Kartik|last6=Rodig|first6=Scott J.|last7=West|first7=Nathan|last8=Xiao|first8=Yun|last9=Brown|first9=Jennifer R.|date=2010-01-05|title=Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/20018760|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=107|issue=1|pages=252–257|doi=10.1073/pnas.0911726107|issn=1091-6490|pmc=2806782|pmid=20018760}}</ref>
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
|''JAK1''
<br />
''JAK2''
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|[https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=109242705 p.V658F][https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=123403459 p.R683G]
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|Recurrent (5-20%)
|<span class="blue-text">EXAMPLE:</span> P
|Unknown
|
|No
|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
|Half of cases with ''CRLF2'' overexpression have activating mutations in ''JAK1'' or ''JAK2'' that promote downstream JAK-STAT signaling;<ref name=":10" /> the  most common mutation, p.R683G, occurs in the pseudokinase domain of ''JAK2'', and less common ''JAK1'' alterations have been detected, which include p.V658F most frequently; clinical trials examining the treatment effects of targeting JAK proteins are currently ongoing.<ref>{{Cite journal|last=Goulart|first=Hannah|last2=Jabbour|first2=Elias|last3=Short|first3=Nicholas J.|last4=Kadia|first4=Tapan M.|last5=Pemmaraju|first5=Naveen|last6=Takahashi|first6=Koichi|last7=Ravandi|first7=Farhad|last8=Konopleva|first8=Marina|last9=Jain|first9=Nitin|date=2025-11|title=A Phase I/II Trial of Ruxolitinib with Chemotherapy for Patients with Relapsed and/or Refractory Philadelphia-like Acute Lymphoblastic Leukemia|url=https://pubmed.ncbi.nlm.nih.gov/40500616|journal=Clinical Lymphoma, Myeloma & Leukemia|volume=25|issue=11|pages=800–807|doi=10.1016/j.clml.2025.05.013|issn=2152-2669|pmid=40500616}}</ref>
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
|''IL7R''
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|Activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|Recurrent (5-20%)
|<span class="blue-text">EXAMPLE:</span> T
|Unknown
|
|No
|
|''IL7R'' is the partner gene of ''CRLF2''; gain-of-function mutations potentiate CRFL2 and its cofactor IL7RA forming a receptor for thymic stromal-derived lymphopoietin, leading to JAK-STAT activation.<ref name=":8">Quesada A, Reynolds M, Jorgensen JL, et al. Cytokine receptor-like factor 2 (CRLF2) expression in precursor B-lymphoblastic leukemia. International Clinical Cytometry Society e-Newsletter. 2014;5(1).</ref>
|-
|-
|
|''SH2B3''
|
''IL2RB''
|
|
|
|
|
|}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>
''TYK2''
In addition to gene translocations, gain-of-function mutations in ''CRLF2'' itself or in its partner gene, ''IL7RA'', have been seen<ref name=":8">Quesada A, Reynolds M, Jorgensen JL, et al. Cytokine receptor-like factor 2 (CRLF2) expression in precursor B-lymphoblastic leukemia. International Clinical Cytometry Society e-Newsletter. 2014;5(1).</ref>.  Alternative alterations activating kinase signaling occur, including activating mutations of ''FLT3'', as well as focal deletions of ''SH2B3'' (also known as ''LNK'')<ref>Tosi S & Reid AG. The Genetic Basis of Haematological Cancers. John Wiley & Sons, Incorporated: Chichester, United Kingdom: 2016.</ref>.


Herold et al. in 2017 reported a wide variety of molecular alterations in BCR-ABL1-like B-ALL, which was shown to have statistically significant associations with alterations of ''IKZF1'', ''CRLF2'', ''JAK2'', ''BTG1'', and high ''CRLF2'' expression<ref name=":5">{{Cite journal|last=Herold|first=Tobias|last2=Schneider|first2=Stephanie|last3=Metzeler|first3=Klaus H.|last4=Neumann|first4=Martin|last5=Hartmann|first5=Luise|last6=Roberts|first6=Kathryn G.|last7=Konstandin|first7=Nikola P.|last8=Greif|first8=Philipp A.|last9=Bräundl|first9=Kathrin|date=2017|title=Adults with Philadelphia chromosome-like acute lymphoblastic leukemia frequently have IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis|url=https://www.ncbi.nlm.nih.gov/pubmed/27561722|journal=Haematologica|volume=102|issue=1|pages=130–138|doi=10.3324/haematol.2015.136366|issn=1592-8721|pmc=5210243|pmid=27561722}}</ref>.
''TLSP''
 
|Activating mutations
<blockquote class="blockedit">
|Oncogene
<center><span style="color:Maroon">'''End of V4 Section'''</span>
|Recurrent (5-20%)
----
|Unknown
</blockquote>
|No
|These result in constitutive activation of JAK-STAT signaling and are often present as multi-subclonal (suggestive of secondary driver events).<ref>{{Cite journal|last=Jain|first=Sarika|last2=Abraham|first2=Anu|date=2020-02|title=BCR-ABL1-like B-Acute Lymphoblastic Leukemia/Lymphoma: A Comprehensive Review|url=https://pubmed.ncbi.nlm.nih.gov/31644323|journal=Archives of Pathology & Laboratory Medicine|volume=144|issue=2|pages=150–155|doi=10.5858/arpa.2019-0194-RA|issn=1543-2165|pmid=31644323}}</ref>
|-
|''RAS'' pathway genes
|Activating mutations
|Oncogenes
|Recurrent (5-20%)
|Unknown
|No
|Activating mutations in ''KRAS'', ''NF1'', ''PTPN11'', and other genes upregulate the MAP kinase pathway and have been found at a higher frequency in B-lymphoblastic  leukaemia/lymphoma with ''BCR::ABL1''-like features compared to other B-lymphoblastic leukaemia/lymphomas.<ref>{{Cite journal|last=Lee|first=Jae Wook|last2=Kim|first2=Yonggoo|last3=Cho|first3=Bin|last4=Kim|first4=Seongkoo|last5=Jang|first5=Pil-Sang|last6=Lee|first6=Jaewoong|last7=Cho|first7=Hanwool|last8=Lee|first8=Gun Dong|last9=Chung|first9=Nack-Gyun|date=2020-07|title=High incidence of RAS pathway mutations among sentinel genetic lesions of Korean pediatric BCR-ABL1-like acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/32378810|journal=Cancer Medicine|volume=9|issue=13|pages=4632–4639|doi=10.1002/cam4.3099|issn=2045-7634|pmc=7333828|pmid=32378810}}</ref>
|}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
==Epigenomic Alterations==
==Epigenomic Alterations==
Not applicable
Not applicable
Line 725: Line 707:
|ABL-class rearrangements  
|ABL-class rearrangements  
|Tyrosine kinase signaling
|Tyrosine kinase signaling
|These result in B-cell progenitor proliferation; may be response to TKIs.<ref>{{Cite journal|last=Senapati|first=Jayastu|last2=Jabbour|first2=Elias|last3=Konopleva|first3=Marina|last4=Short|first4=Nicholas J.|last5=Tang|first5=Guilin|last6=Daver|first6=Naval|last7=Kebriaei|first7=Partow|last8=Kadia|first8=Tapan|last9=Pemmaraju|first9=Naveen|date=2023-05|title=Philadelphia-Like Genetic Rearrangements in Adults With B-Cell ALL: Refractoriness to Chemotherapy and Response to Tyrosine Kinase Inhibitor in ABL Class Rearrangements|url=https://pubmed.ncbi.nlm.nih.gov/37196217|journal=JCO precision oncology|volume=7|pages=e2200707|doi=10.1200/PO.22.00707|issn=2473-4284|pmc=10309573|pmid=37196217}}</ref>
|These result in B-cell progenitor proliferation; may be responsive to TKIs.<ref>{{Cite journal|last=Senapati|first=Jayastu|last2=Jabbour|first2=Elias|last3=Konopleva|first3=Marina|last4=Short|first4=Nicholas J.|last5=Tang|first5=Guilin|last6=Daver|first6=Naval|last7=Kebriaei|first7=Partow|last8=Kadia|first8=Tapan|last9=Pemmaraju|first9=Naveen|date=2023-05|title=Philadelphia-Like Genetic Rearrangements in Adults With B-Cell ALL: Refractoriness to Chemotherapy and Response to Tyrosine Kinase Inhibitor in ABL Class Rearrangements|url=https://pubmed.ncbi.nlm.nih.gov/37196217|journal=JCO precision oncology|volume=7|pages=e2200707|doi=10.1200/PO.22.00707|issn=2473-4284|pmc=10309573|pmid=37196217}}</ref>
|-
|-
|''CRLF2'' overexpression; mutations of ''CRLF2'', ''JAK1'', ''IL7R, SH2B3, IL2RB, and TYK2''; ''JAK2'' and ''EPOR'' rearrangements
|''CRLF2'' overexpression; mutations of ''CRLF2'', ''JAK1/2'', ''IL7R, SH2B3, IL2RB, TYK2,'' and ''TLSP''; ''JAK2'' and ''EPOR'' rearrangements
|JAK-STAT signaling
|JAK-STAT signaling
|CRFL2 and its cofactor IL7RA form a receptor for thymic stromal-derived lymphopoietin that activates the JAK2-signal transducer and upregulates the transcription 5 pathway<ref name=":8" />; other mutations not in ''CRLF2'' and ''IL7R'' result in constitutive JAK/STAT activation downstream of CRLF2.  
|These potentiate the JAK2-signal transducer and upregulate the transcription 5 pathway;<ref name=":8" /> other mutations not in ''CRLF2'' and ''IL7R'' cause constitutive JAK/STAT activation downstream of CRLF2.  
|-
|-
|''IKZF1'' deletion
|''IKZF1'' deletion
Line 740: Line 722:
*Flow cytometry for ''CRLF2'' has been shown in some studies to be 100% concordant with FISH results<ref name=":7" />.
*Flow cytometry for ''CRLF2'' has been shown in some studies to be 100% concordant with FISH results<ref name=":7" />.
*Next-generation sequencing is helpful for detecting copy number changes, single nucleotide variants, and gene fusions involving ''CRLF2'', ''ABL1'', ''ABL2'', ''JAK2'', etc.
*Next-generation sequencing is helpful for detecting copy number changes, single nucleotide variants, and gene fusions involving ''CRLF2'', ''ABL1'', ''ABL2'', ''JAK2'', etc.
*Gene expression profile algorithms, incorporating prediction analysis or hierarchical clustering of microarrays, provide the definitive diagnosis of B-lymphoblastic leukaemia/lymphoma with ''BCR::ABL1''-like features.
*Gene expression profile algorithms, incorporating prediction analysis or hierarchical clustering of microarrays, provide a definitive diagnosis of B-lymphoblastic leukaemia/lymphoma with ''BCR::ABL1''-like features.


==Familial Forms==
==Familial Forms==
Families with certain inherited variants of ''GATA3'' (often seen in Native-American populations) are at increased risk of B-lymphoblastic leukaemia/lymphoma with ''BCR::ABL1''-like features<ref>{{Cite journal|last=Perez-Andreu|first=Virginia|last2=Roberts|first2=Kathryn G.|last3=Harvey|first3=Richard C.|last4=Yang|first4=Wenjian|last5=Cheng|first5=Cheng|last6=Pei|first6=Deqing|last7=Xu|first7=Heng|last8=Gastier-Foster|first8=Julie|last9=E|first9=Shuyu|date=2013|title=Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse|url=https://www.ncbi.nlm.nih.gov/pubmed/24141364|journal=Nature Genetics|volume=45|issue=12|pages=1494–1498|doi=10.1038/ng.2803|issn=1546-1718|pmc=4039076|pmid=24141364}}</ref>.
Families with certain inherited variants of ''GATA3'' (often seen in Native-American populations) are at increased risk of B-lymphoblastic leukaemia/lymphoma with ''BCR::ABL1''-like features.<ref>{{Cite journal|last=Perez-Andreu|first=Virginia|last2=Roberts|first2=Kathryn G.|last3=Harvey|first3=Richard C.|last4=Yang|first4=Wenjian|last5=Cheng|first5=Cheng|last6=Pei|first6=Deqing|last7=Xu|first7=Heng|last8=Gastier-Foster|first8=Julie|last9=E|first9=Shuyu|date=2013|title=Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse|url=https://www.ncbi.nlm.nih.gov/pubmed/24141364|journal=Nature Genetics|volume=45|issue=12|pages=1494–1498|doi=10.1038/ng.2803|issn=1546-1718|pmc=4039076|pmid=24141364}}</ref>  


==Additional Information==
==Additional Information==
Line 768: Line 750:
==References==
==References==
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span> <references />
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span> <references />
<br />


==Notes==
==Notes==
Line 775: Line 755:


Prior Author(s):  Fabiola Quintero-Rivera, MD   
Prior Author(s):  Fabiola Quintero-Rivera, MD   
          
          
<nowiki>*</nowiki>''Citation of this Page'': “B-lymphoblastic leukaemia/lymphoma with BCR::ABL1-like features”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:B-lymphoblastic_leukaemia/lymphoma_with_BCR::ABL1-like_features</nowiki>.
<nowiki>*</nowiki>''Citation of this Page'': “B-lymphoblastic leukaemia/lymphoma with BCR::ABL1-like features”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:B-lymphoblastic_leukaemia/lymphoma_with_BCR::ABL1-like_features</nowiki>.
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