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> 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.   

| rowspan="12" |''[[ABL1]]''

| rowspan="3" |''[[ABL2]]''

| rowspan="2" |''[[CRLF2]]''

| rowspan="3" |''CSF1R''

|''DGKH'' (13q14.1)

| rowspan="4" |''EPOR'' (19p13.2)

|''IL2RB'' (22q12.3)

| rowspan="22" |''[[JAK2]]''

|''[[PDGFRA]]''

| rowspan="8" |''[[PDGFRB]]'' (5q32)

| rowspan="3" |''PTK2B'' (8p21.2)

| rowspan="3" |''TYK2'' (19p13.2)

|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>

|chr9:21,967,752-21,995,324

|''CDKN2A''

''CDKN2B''

|These changes cause ''CRLF2'' overexpression, upregulating the JAK-STAT pathway.

|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.

|Polysomy or iAMP21  

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

|P

|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>

[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]

|''CRLF2''

|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>

|''JAK1''

|[https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=109242705 p.V658F][https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=123403459 p.R683G]

|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>

|''IL7R''

|Activating mutations

|Oncogene

|Recurrent (5-20%)

|Unknown

|''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''

''TYK2''

|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 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

|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'', ''JAK1/2'', ''IL7R, SH2B3, IL2RB, TYK2,'' and ''TLSP''; ''JAK2'' and ''EPOR'' rearrangements

|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.  

*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.

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>