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

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.   

|These changes cause ''CRLF2'' overexpression; CRFL2 and its cofactor IL7RA form a receptor for thymic stromal-derived lymphopoietin, upregulating the JAK-STAT pathway.

|These changes stem from telomere attrition that result in the amplification of all or a region on chromosome 21.

|Unknown

|Deletion of ''PAX5'' results in altered B-cell development.<ref name=":4" />

|<span class="blue-text">EXAMPLE:</span>''EGFR''

 

<br />

|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations

|<span class="blue-text">EXAMPLE:</span> Oncogene

|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)

|<span class="blue-text">EXAMPLE:</span> T

|<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

|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations

|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene

|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)

|<span class="blue-text">EXAMPLE:</span> P

|

|<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.

|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations

|<span class="blue-text">EXAMPLE:</span> Activating mutations

|<span class="blue-text">EXAMPLE:</span> Oncogene

|<span class="blue-text">EXAMPLE:</span> Common (melanoma)

|<span class="blue-text">EXAMPLE:</span> T

|

|

|

|

|

|

|

|}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.

 

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>.

 

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|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>

|''CRLF2'' overexpression; mutations of ''CRLF2'', ''JAK1'', ''IL7R, SH2B3, IL2RB, and TYK2''; ''JAK2'' and ''EPOR'' rearrangements

|These result in upregulation of 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.