Molecular basis and clinical significance of genetic aberrations in B-cell precursor acute lymphoblastic leukemia

Ghazavi, Farzaneh; Lammens, Tim; Roy, Nadine Van; Poppe, Bruce; Speleman, Franki; Benoît, Yves; Vlierberghe, Pieter Van; Moerloose, Barbara De

doi:10.1016/j.exphem.2015.05.015

Cited by 24 publications

(28 citation statements)

References 166 publications

(168 reference statements)

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“…In the present work BCR/ABL fusion was detected in 11 patients (28.2%). This is in concordance with Ghazavi F et al [3] who reported that BCR/ABL fusion gene is presented with an incidence about 30% in adult but slightly higher than Noreen et al [9] who reported that BCR/ABL fusion gene is detected with an incidence 20.3%.…”

Section: Discussionsupporting

confidence: 91%

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Prognostic Features of BCR-ABL Genetic Variations in Acute Lymphoblastic Leukemia

Fouad¹,

Abo-Elwafa²,

Aziz³

et al. 2018

OJBD

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Background: Acute lymphoblastic leukemia (ALL) is a hematologic malignancy which results from accumulation of lymphoid progenitor cells in the bone marrow and/or extramedullary sites. Philadelphia chromosome (Ph 1) positive ALL, a high-risk cytogenetic subset, accounts for 25%-30% of adult ALL cases but occurs in less than 5% of children. We aimed with this study to detect BCR-ABL genes fusion, amplification and deletion in ALL patients, using extrasignal-fluorescence in situ hybridization (ES-FISH), and to assess their relation with other standard prognostic factors and therapeutic response. Patients and Methods: This study was carried out on 39 newly diagnosed ALL patients. All patients were subjected to: history, clinical examination and laboratory investigations, which included complete blood count (CBC), peripheral blood (PB), bone marrow (BM) examination, immunophenotyping and fluorescence in situ hybridization using extra-signal probe to detect BCR-ABL genes fusion. Results: This study showed statistical analysis of patients' t(9; 22) with other factors revealed, significant association (p < 0.05) of t(9; 22) with patients outcome, age > 35 years, hepatosplenomegaly, absence of lymphadenopathy, TLC ≥ 50 × 10 9 /L, absolute PB blasts ≥ 4.4 × 10 9 /L, immunophenotyping and other aberrations. Conclusion: BCR/ABL fusion gene analysis by ES-FISH may serve as a prognostic marker in adulthood ALL. The age, TLC and t(9; 22) represent the significant standard prognostic factors in relation to patients' outcome.

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Section: Discussionsupporting

confidence: 91%

“…Adult and childhood ALL differ markedly in the prevalence of various cytogenetic abnormalities. Philadelphia chromosome (Ph 1 ) positive ALL, a high-risk cytogenetic subset, accounts for 25% -30% of adult ALL cases but occurs in less than 5% of children [3].…”

Section: Introductionmentioning

confidence: 99%

Prognostic Features of BCR-ABL Genetic Variations in Acute Lymphoblastic Leukemia

Fouad¹,

Abo-Elwafa²,

Aziz³

et al. 2018

OJBD

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“…For example, simultaneous trisomies of 4,10 and 17 carry the best prognosis [ 16 ]. Gain of chromosomes 4, 6, 10, and 17 indicates good prognosis [ 17 ], while gain of chromosome 5 or isochromosome 17 indicates poorer prognosis in this group [ 18 ]. Abnormality of t(12;21)/ ETV6-RUNX1 is usually cryptic by conventional karyotyping but detectable by fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR).…”

Section: B-all Cytogentic Abnormalitties and Subclassificationmentioning

confidence: 99%

B lymphoblastic leukemia/lymphoma: new insights into genetics, molecular aberrations, subclassification and targeted therapy

et al. 2017

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B lymphoblastic leukemia/lymphoma (B-ALL) is a clonal hematopoietic stem cell neoplasm derived from B-cell progenitors, which mostly occurs in children and adolescents and is regarded as one of top leading causes of death related to malignancies in this population. Despite the majority of patients with B-ALL have fairly good response to conventional chemotherapeutic interventions followed by hematopoietic stem cell transplant for the last decades, a subpopulation of patients show chemo-resistance and a high relapse rate. Adult B-ALL exhibits similar clinical course but worse prognosis in comparison to younger individuals. Ample evidences have shown that the clinical behavior, response rate and clinical outcome of B-ALL rely largely on its genetic and molecular profiles, such as the presence of BCR-ABL1 fusion gene which is an independent negative prognostic predictor. New B-ALL subtypes have been recognized with recurrent genetic abnormalities, including B-ALL with intrachromosomal amplification of chromosome 21 (iAMP21), B-ALL with translocations involving tyrosine kinases or cytokine receptors (“BCR-ABL1-like ALL”). Genome-wide genetic profiling studies on B-ALL have extended our understanding of genomic landscape of B-ALL, and genetic mutations involved in various key pathways have been illustrated. These include CRLF2 and PAX5 alterations, TP53, CREBBP and ERG mutations, characteristic genetic aberrations in BCR-ABL1-like B-ALL and others. The review further provides new insights into clinical implication of the genetic aberrations in regard to targeted therapy development.

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“…Overexpression of CRLF2 is present in up to 15% of high risk BCP-ALL patients [5] and 50% of both Down Syndrome-associated BCP-ALL and Ph-like BCP-ALL patients [8][9][10]. Subsets of CRLF2-overexpressing cells have been shown to also harbor activating mutations in JAK, IL7R and NRAS [11], as well as deletions of the IKZF1 gene [12,13], which similarly confer poor clinical prognosis [14].…”

Section: Introductionmentioning

confidence: 99%

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2018

Oncotarget

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Children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) overexpressing the CRLF2 gene (hiCRLF2) have poor prognosis. CRLF2 protein overexpression leads to activated JAK/STAT signaling and trials are underway using JAK inhibitors to overcome treatment failure. Pre-clinical studies indicated limited efficacy of single JAK inhibitors, thus additional pathways must be targeted in hiCRLF2 cells. To identify additional activated networks, we used single-cell mass cytometry to examine 15 BCP-ALL primary patient samples. We uncovered a coordinated signaling network downstream of CRLF2 characterized by co-activation of JAK/STAT, PI3K, and CREB pathways. This CRLF2-driven network could be more effectively disrupted by SRC/ABL inhibition than single-agent JAK or PI3K inhibition, and this could be demonstrated even in primary minimal residual disease (MRD) cells. Our study suggests SCR/ABL inhibition as effective in disrupting the cooperative functional networks present in hiCRLF2 BCP-ALL patients, supporting further investigation of this strategy in pre-clinical studies.

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Molecular basis and clinical significance of genetic aberrations in B-cell precursor acute lymphoblastic leukemia

Cited by 24 publications

References 166 publications

Prognostic Features of BCR-ABL Genetic Variations in Acute Lymphoblastic Leukemia

Prognostic Features of BCR-ABL Genetic Variations in Acute Lymphoblastic Leukemia

B lymphoblastic leukemia/lymphoma: new insights into genetics, molecular aberrations, subclassification and targeted therapy

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