A novel integrated cytogenetic and genomic classification refines risk stratification in pediatric acute lymphoblastic leukemia

Moorman, Anthony V.; Enshaei, Amir; Schwab, Claire; Wade, Rachel; Chilton, Lucy; Elliott, Alannah; Richardson, Stacey; Hancock, Jeremy; Kinsey, Sally; Mitchell, Christopher; Goulden, Nicholas; Vora, Ajay; Harrison, Christine J.

doi:10.1182/blood-2014-03-562918

Cited by 179 publications

(241 citation statements)

References 37 publications

(50 reference statements)

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“…The IKZF1 deletions accounted for 16, and 26% of the patients with IKZF1 deletions were categorized as the IK6 subtype (4-7 exons deletion). A similar method of detection was observed in 1,644 cases among British children with ALL in 2014 (11). CDKN2A/2B and ETV6 are the commonly (20-25%) deleted genes in children with ALL; and IKZF1 and PAX5 gene deletions occurred simultaneously in 15% of patients.…”

Section: Discussionmentioning

confidence: 77%

Prognostic significance of copy number alterations detected by multi‑link probe amplification of multiple genes in adult acute lymphoblastic leukemia

Fang

Tian

et al. 2018

Oncol Lett

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Abstract. The multiplex ligation-dependent probe amplification (MLPA) method was used to detect the copy number alterations (CNAs) of IKAROS family zinc finger 1 (IKZF1), paired box 5 (PAX5), ETS variant 6 (ETV6), RB transcriptional corepressor 1 (RB1), BTG anti-proliferation factor 1 (BTG1), early B-cell factor 1 (EBF1), cyclin dependent kinase inhibitor 2A/2B (CDKN2A/2B) and cytokine receptor like factor 2 (CRLF2) genes in 87 adults with acute lymphoblastic leukemia (ALL) in China. The effects of CNAs on prognosis were analyzed. Gene deletions were detected in 58/87 (66.7%) ALL patients. The most common deletions were observed in the following genes: IKZF1 (40.6%), CDKN2A (31.9%), CDKN2B (29%), PAX5 (21.7%), RB1 (14.5%) and BTG1 (10.1%). B cell-ALL (B-ALL) patients with CDKN2A/2B deletions exhibited poor 2-year overall survival (OS; P=0.055) and relapse-free survival (RFS; P=0.054) rates. CDKN2A/2B deletions were associated with poor 2-year OS (P=0.045) and RFS (P= 0.071) rates in Philadelphia chromosome positive (Ph

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Section: Discussionmentioning

confidence: 77%

Prognostic significance of copy number alterations detected by multi‑link probe amplification of multiple genes in adult acute lymphoblastic leukemia

Fang

Tian

et al. 2018

Oncol Lett

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“…Besides the involvement of ABL1, these cases have a similar profile of secondary aberrations including frequent deletions of IKZF1, CDKN2A/B, PAX5, BTG1 and RB1 which distinguish them from other ALL. [49][50][51] We have previously shown the prenatal origin of ETV6-ABL1 in a 5-year old child with ALL 20 demonstrating the need for cooperating mutations to induce an overt disease. The two most frequent secondary aberrations in ETV6-ABL1 ALL (CDKN2A/B and IKZF1 loss) have both been shown to cooperate with BCR-ABL1 during leukemogenesis in mice and likely represent cooperating lesions also in ETV6-ABL1 leukemia.…”

Section: Discussionmentioning

confidence: 99%

Characterization of leukemias with ETV6-ABL1 fusion

et al. 2016

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T o characterize the incidence, clinical features and genetics of ETV6-ABL1 leukemias, representing targetable kinase-activating lesions, we analyzed 44 new and published cases of ETV6-ABL1-positive hematologic malignancies [22 cases of acute lymphoblastic leukemia (13 children, 9 adults) and 22 myeloid malignancies (18 myeloproliferative neoplasms, 4 acute myeloid leukemias)]. The presence of the ETV6-ABL1 fusion was ascertained by cytogenetics, fluorescence in-situ hybridization, reverse transcriptase-polymerase chain reaction and RNA sequencing. Genomic and gene expression profiling was performed by single nucleotide polymorphism and expression arrays. Systematic screening of more than 4,500 cases revealed that in acute lymphoblastic leukemia ETV6-ABL1 is rare in childhood (0.17% cases) and slightly more common in adults (0.38%). There is no systematic screening of myeloproliferative neoplasms; however, the number of ETV6-ABL1-positive cases and the relative incidence of acute lymphoblastic leukemia and myeloproliferative neoplasms suggest that in adulthood ETV6-ABL1 is more common in BCR-ABL1-negative chronic myeloid leukemia-like myeloproliferations than in acute lymphoblastic leukemia. The genomic profile of ETV6-ABL1 acute lymphoblastic leukemia resembled that of BCR-ABL1 and BCR-ABL1-like cases with 80% of patients having concurrent CDKN2A/B and IKZF1 deletions. In the gene expression profiling all the ETV6-ABL1-positive samples clustered in close vicinity to BCR-ABL1 cases. All but one of the cases of ETV6-ABL1 acute lymphoblastic leukemia were classified as BCR-ABL1-like by a standardized assay. Over 60% of patients died, irrespectively of the disease or age subgroup examined. In conclusion, ETV6-ABL1 fusion occurs in both lymphoid and myeloid leukemias; the genomic profile and clinical behavior resemble BCR-ABL1-positive malignancies, including the unfavorable prognosis, particularly of acute leukemias. The poor outcome suggests that treatment with tyrosine kinase inhibitors should be considered for patients with this fusion.

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“…Here a CNA profile based on the presence or absence of the eight most frequently deleted genes segregates patients with intermediate-risk cytogenetics (mostly Bother) into two new genetic risk groups (Figure 4). 88 The prognosis of patients with good-or high-risk cytogenetics was unaffected by their CNA profile. However, intermediate cytogenetic risk patients, separated into two subgroups (good risk vs. intermediate-/high-risk CNA profile) with differential OS rates (98% vs. 87%).…”

Section: Copy Number Alteration Profilingmentioning

confidence: 99%

“…However, intermediate cytogenetic risk patients, separated into two subgroups (good risk vs. intermediate-/high-risk CNA profile) with differential OS rates (98% vs. 87%). 88 Thus, this approach has identified a group of B-other ALL patients with a good-risk CNA profile and a very low risk of relapse who potentially could be considered for treatment deintensification. The validity of such an approach is supported by observations that the prognostic effect of IKZF1 deletions depends on the presence/absence of other deletions (e.g.…”

Section: Copy Number Alteration Profilingmentioning

confidence: 99%

New and emerging prognostic and predictive genetic biomarkers in B-cell precursor acute lymphoblastic leukemia

2016

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A novel integrated cytogenetic and genomic classification refines risk stratification in pediatric acute lymphoblastic leukemia

Abstract: Key Points• Integrating cytogenetic and genomic data in pediatric ALL reveals 2 subgroups with different outcomes independent of other risk factors.• A total of 75% of children on UKALL2003 had a good-risk genetic profile, which predicted an EFS and OS of 94% and 97% at 5 years.

Cited by 179 publications

References 37 publications

Prognostic significance of copy number alterations detected by multi‑link probe amplification of multiple genes in adult acute lymphoblastic leukemia

Prognostic significance of copy number alterations detected by multi‑link probe amplification of multiple genes in adult acute lymphoblastic leukemia

Characterization of leukemias with ETV6-ABL1 fusion

New and emerging prognostic and predictive genetic biomarkers in B-cell precursor acute lymphoblastic leukemia

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