View source for Page:B-lymphoblastic leukemia/lymphoma, BCR-ABL1-like

Title of Page
B-lymphoblastic leukemia/lymphoma, BCR-ABL1-like

Primary Author(s)*
Mark Evans, MD
University of California, Irvine

Fabiola Quintero-Rivera, MD
University of California, Los Angeles

Cancer Category/Type
Acute lymphoblastic leukemia

Cancer Sub-Classification / Subtype
B-lymphoblastic leukemia/lymphoma, BCR-ABL1-like

Definition / Description of Disease
In 2009, a high-risk subgroup of B-ALL was identified in children, adolescents, and young adults [1-3]. The genetic expression is similar to that of BCR-ABL1-positive cases, but without t(9;22)(q34.1;q11.2). Instead, BCR-ABL-1-like B-ALL is a genetically heterogenous disease, often with alterations activating cytokine receptors and tyrosine kinases. Several genetic expression profiles were initially utilized to recognize cases [4-5], however, different profiles did not always identify the same patients [6]. Although emerging data advocates the therapeutic use of tyrosine kinase or JAK inhibitors in this disease process, BCR-ABL-like B-ALL is often associated with very high rates of relapse and poor overall survival; thus proper diagnosis is essential [7].     

Synonyms / Terminology
Ph-like B-lymphoblastic leukemia/lymphoma

Epidemiology / Prevalence
	Ph-like ALL comprises up to 15% of childhood B-ALL, and 20 to 25% in adolescents and young adults [8].
	The incidence in adult patients is controversial—from 13-17% to up to 33% in some reports [9-11].
	Higher rates of disease are observed in Hispanic and Native-American populations, and among children with Down syndrome [12].

Clinical Features
The presenting symptoms are similar to those of other ALL patients, with the exception of potentially higher white blood cell counts [13].

Sites of Involvement
Bone marrow

Morphologic Features
There are no morphological or cytochemical features that aid in the diagnosis. Blasts range from small to large and chromatin varying from immature to more mature, corresponding to French-American-British classification L1 or L2 subtype [14].

Immunophenotype
Blasts are typically CD19, TdT, and CD10-positive. By flow cytometry, a subset of cases with CRLF2 translocations show very high levels of surface protein expression [13].
 
Chromosomal Rearrangements (Gene Fusions)
Tyrosine kinase-type translocations are common and involve ABL1 and other kinases (such as ABL2, EPOR, JAK2, PDGFRB, and CSF1R); more than 30 gene partners have been described.  Frequently reported examples include IGH–EPOR of the t(14;19)(q32;p13)/ins(14;19)(q32;p13), EBF1–PDGFRB of the del(5)(q32q33.3), NUP214–ABL1 of the t(9;9)(q34;q34)/del(9)(q34q34), and ETV6–ABL1 of the t(9;12)(q34;p13). Other notable fusions are BCR–JAK2 , PAX5–JAK2 , STRN3–JAK2 , RANBP2–ABL1 , RCSD1–ABL1 , and MEF2D–CSF1R [15].
	
Characteristic Chromosomal Aberrations / Patterns
Approximately half of cases demonstrate rearrangements resulting in overexpression of CRLF2 [14]. 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.

CRLF2 rearrangements rarely occur in case with kinase translocations [13].

Approximately half of case with CRLF2 expression have concomitant JAK-STAT mutations (most common, JAK2 R683G).

Genomic Gain/Loss/LOH
Monoallelic (often partial) deletion of the IKAROS transcription factor, encoded by IKZF1, is one of the most frequently observed genetic abnormalities in BCR-ABL1-like B-ALL, although this finding is not specific and not included in the definition [6]. 

Gene Mutations (SNV/INDEL)
In addition to gene translocations, gain-of-function mutations in CRLF2 itself or in its partner gene, IL7RA, have been seen [16].
Alternative alterations activating kinase signaling occur, including activating mutations of FLT3, as well as focal deletions of SH2B3 (also known as LNK) [17].

	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 [18].		 	

Epigenomics (Methylation)
Not applicable

Genes and Main Pathways Involved
	IKAROS transcription factor:  Deletion of IKZF1 results in activation of EBF1, MSH2, and MCL1, leading to B-cell leukemogenesis [19]
	CRLF2 overexpression:  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 [16].
	Dysregulation of several tyrosine kinase signaling pathways (involving ABL1, ABL2, PDGFRB, CSF1, etc.) results in B-cell progenitor proliferation.

Diagnostic Testing Methods
	Flow cytometry for CRLF2 has been shown in some studies to be 100% concordant with FISH results [14].
	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 hierarchal clustering of microarrays, provide the definitive diagnosis of BCR-ABL1-like B-ALL.

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
	Diagnosis:  Definitive diagnosis is based on two major gene expression signatures (DCOG/Erasmus MC and COG/St. Jude).
o	DCOG/Erasmus MC incorporates hierarchal clustering of microarrays using a 110-gene probe set; this genetic signature frequently detected deletions in IKZF1, dic(9;20), and iAMP21 in BCR-ABL1-like B-ALL [4].
o	COG/St. Jude employs predictive analysis of microarrays using a 257-gene probe set; this genetic signature demonstrated primarily activating kinase or cytokine receptor signaling alterations, in addition to IKZF1 deletions [5].
	Prognosis:  In both pediatric and adult populations, BCR-ABL1-like B-ALL is associated with high rates of relapse and poor prognosis.
o	The median 5-year overall survival rates for children with BCR-ABL1-like B-ALL, adolescents, and young adults was 72.8%, 65.8%, and 25.8%, respectively [20].
o	Median 5-year-overall survival in adults was 22%, versus 64% in comparable patients with non-BCR-ABL1, non-BCR-ABL1-like, and non-MLL translocation B-ALL [18].
	Therapeutic Implications:  Due to the aggressive nature of the disease, patients are often treated with high-intensity chemotherapy regimens, such as hyper-CVAD or an augmented Berlin-Frankfurt-Münster regimen [11].
o	However, given the high incidence of fusions involving JAK2, ABL1, ABL2, and other tyrosine kinases, tyrosine kinase inhibitors and JAK inhibitors are now being trialed clinically [20-22].  

Familial Forms
Families with certain inherited variants of GATA3 (often seen in Native-American populations) are at increased risk of BCR-ABL1-like B-ALL [23]. 


Links
CRLF2 in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/?term=%22crlf2%22%5Bgene%5D)
Pre-B ALL B-lymphoblastic leukemia/lymphoma with BCR-ABL1-like/Ph-like in Pathology Outlines (http://www.pathologyoutlines.com/topic/leukemiaprebbcrabl1like.html)

References
1.	Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 2009;10(2):125-134.
2.	Mullighan CG, Su X, Zhang J, et al. Children’s Oncology Group. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470-480.
3.	Roberts KG, Morin RD, Zhang J, et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell. 2012;22(2):153-166.
4.	Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 2009;10:125–134.
5.	Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470–480.
6.	Boer JM, Marchante JR, Evans WE, et al. BCR-ABL1-like cases in pediatric acute lymphoblastic leukemia: A comparison between DCOG/Erasmus MC and COG/St. Jude signatures. Haematologica. 2015;100:e354–e357.
7.	Roberts KG, Reshmi SC, Harvey RC, et al. Genomic and outcome analyses of Ph-like ALL in NCI standard-risk patients: a report from the Children's Oncology Group. Blood. 2018;132(8):815–24.
8.	Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014;371(11):1005-1015.
9.	Boer JM, Koenders JE, van der Holt B, et al. Expression profiling of adult acute lymphoblastic leukemia identifies a BCR-ABL1-like subgroup characterized by high non-response and relapse rates. Haematologica. 2015;100(7):e261-e264. 
10.	Herold T, Schneider S, Metzeler KH, Neumann M, Hartmann L, Roberts KG, Konstandin NP, Greif PA, Bräundl K, Ksienzyk B, et al. Adults with Philadelphia chromosome-like acute lymphoblastic leukemia frequently have IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis. Haematologica. 2017;102:130–138.
11.	Jain N., Roberts K. G., Jabbour E., et al. Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults. Blood. 2017;129(5):572–581.
12.	Harvey RC, Mullighan CG, Chen IM, Wharton W, Mikhail FM, Willman CL. Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood. 2010;115:5312–21.
13.	Swerdlow SH, Campo E, Harris NL, Jaffe ES, et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th Edition. IARC Press: Lyon, France. 2016.
14.	Konoplev S, Lu X, Konopleva M, Jain N, Ouyang J, Goswami M, Roberts KG, Valentine M, Mullighan CG, Bueso-Ramos C1, et al. CRLF2-positive B-cell acute lymphoblastic leukemia in adult patients: A single-institution experience. Am J Clin Pathol. 2017;147:357–363.
15.	Heim S & Mitelman F. Cancer Cytogenetics: Chromosomal and Molecular Genetic Aberrations of Tumor Cells. John Wiley & Sons, Incorporated: Chichester, United Kingdom. 2015.
16.	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).
17.	Tosi S & Reid AG. The Genetic Basis of Haematological Cancers. John Wiley & Sons, Incorporated: Chichester, United Kingdom: 2016.
18.	Herold T, Schneider S, Metzeler K, et al. Adults with Philadelphia chromosome-like acute lymphoblastic leukemia in adults have frequent IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis. Haematologica 2017;102(1):130–138.
19.	Van Der Veer A, Waanders E, Pieters R, Willemse ME, Van Reijmersdal S V., Russell LJ, et al. Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL. Blood. 2013;122: 2622–2629.
20.	Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014;371(11):1005-1015.
21.	Tasian SK, Doral MY, Borowitz MJ, Wood BL, Chen IM, Harvey RC, Gastier-Foster JM, Willman CL, Hunger SP, Mullighan CG, et al. Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia. Blood. 2012;120:833–842.
22.	Iacobucci I, Li Y, Roberts KG, et al. Truncating erythropoietin receptor rearrangements in acute lymphoblastic leukemia. Cancer Cell. 2016;29(2):186-200.
23.	Perez-Andreu V., Roberts K.G., Harvey R.C. et al. Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse. Nat. Genet. 2013;45:1494–1498. 

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