Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome

Harvey, Richard C.; Mullighan, Charles G.; Wang, Xuefei; Dobbin, Kevin K.; Davidson, George S.; Bedrick, Edward J.; Chen, I‐Ming; Atlas, Susan R.; Kang, Huining; Ar, Kerem; Wilson, Carla S.; Wharton, Walker; Murphy, Maurice H.; Devidas, Meenakshi; Carroll, Andrew J.; Borowitz, Michael J.; Bowman, W. Paul; Downing, James R.; Relling, Mary V.; Yang, Jun J.; Bhojwani, Deepa; Carroll, William L.; Camitta, Bruce M.; Reaman, Gregory H.; Smith, Malcolm A.; Hunger, Stephen P.; Willman, Cheryl L.

doi:10.1182/blood-2009-08-239681

Cited by 363 publications

(399 citation statements)

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“…34 Furthermore, while concluding the current report, a study was published analyzing the genetic basis for relapse in 207 uniformly treated children with high-risk preB-ALL. 35 This study revealed eight unique genetic clusters within high-risk ALL patients, of which the expression of Fat1 was highly ranked (59th) within cluster R2, a cluster also associated with the t(1;19)(E2A-PBX1) translocation; however, we found that Fat1 within this cohort was not prognostic on its own for overall survival (data not shown). This does not contradict the work presented in the current manuscript where Fat1 expression was found to be an independent prognostic marker in paired diagnosis-relapse patients, but yields important information behind the biology of relapse, information that continues to be needed to successfully cure the patients whom relapse.…”

Section: Discussionmentioning

confidence: 62%

The Fat1 cadherin is overexpressed and an independent prognostic factor for survival in paired diagnosis–relapse samples of precursor B-cell acute lymphoblastic leukemia

et al. 2011

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Improved survival of patients with acute lymphoblastic leukemia (ALL) has emerged from identifying new prognostic markers; however, 20% of children still suffer recurrence. Previously, the altered expression of Fat1 cadherin has been implicated in a number of solid tumors. In this report, in vitro analysis shows that Fat1 protein is expressed by a range of leukemia cell lines, but not by normal peripheral blood (PB) and bone marrow (BM) cells from healthy donors. In silico analysis of expression of array data from clinical leukemias found significant levels of Fat1 transcript in 11% of acute myeloid leukemia, 29% and 63% of ALL of B and T lineages, respectively, and little or no transcript present in normal PB or BM. Furthermore, in two independent studies of matched diagnosis --relapse of precursor B-cell (preB) ALL pediatric samples (n ¼ 32 and n ¼ 27), the level of Fat1 mRNA expression was prognostic at the time of diagnosis. High Fat1 mRNA expression was predictive of shorter relapse-free and overall survival, independent of other traditional prognostic markers, including white blood cell count, sex and age. The data presented demonstrate that Fat1 expression in preB-ALL has a role in the emergence of relapse and could provide a suitable therapeutic target in high-risk preB-ALL.Leukemia ( INTRODUCTIONChildren with acute lymphoblastic leukemia (ALL) continue to suffer a 20% incidence of relapse after treatment with the best available therapy. High-resolution genomic profiling, including analysis of single-nucleotide polymorphisms and copy number abnormalities, has greatly aided an understanding of the molecular mechanisms underlying treatment outcome, therapy response and the biology of relapse. 1,2 For precursor B-cell (preB) ALL, genomic studies have shown that copy number abnormalities in genes involved in lymphoid differentiation and cell cycle control are common, with deletions, or part thereof, found in PAX5, EBF1, IKZF1, TCF-4, CDKN2A and RB1. 2 --5 Recent reports also indicate that deletions and nonsense mutations of the IKZF1 gene are significantly associated with poor relapse-free and overall survival rates in preB-ALL. 6 However, in light of these studies, questions remain on the biology of relapse, with marker analysis complicated by the fact that phenotypic shifts in preB-ALL blasts can occur between diagnostic and post-chemotherapy or relapse samples. 7 Those cells that give rise to relapse in some cases appear to be selected during treatment, with clonal evolution occurring of a minor subclone present at diagnosis rather than simply being the development of chemotherapeutic resistance of the original leukemic clone. 8,9 The inherent genetic heterogeneity

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Section: Discussionmentioning

confidence: 62%

The Fat1 cadherin is overexpressed and an independent prognostic factor for survival in paired diagnosis–relapse samples of precursor B-cell acute lymphoblastic leukemia

et al. 2011

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“…In line with this observation, multiple deletions in lymphoid development genes are frequently observed in Ph-like patients. 22,23,25 IKZF1 deletions were identified as an independent prognostic factor for CIR in the whole series but not in the Ph-negative subgroup. The low number of Phpositive patients does not allow specific conclusions to be drawn regarding the prognosis.…”

Section: Discussionmentioning

confidence: 77%

“…EBF1 losses were enriched in the ETV6-RUNX1 subtype (the most common cytogenetic aberration in childhood B-cell ALL), although this is rarely observed in adult Bcell ALL. 4 Harvey et al 22 showed that EBF1 deletions were present in only the 2 poorest outcome groups in a series of 207 children with high-risk ALL, and they correlated with the BCR-ABL1-like signature. Den Boer et al 23 showed that EBF1 deletions were exclusively present in the BCR-ABL1-like subtype and were associated with resistance to L-asparaginase and daunorubicin.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of copy number alterations in adolescent and adult patients with precursor B acute lymphoblastic leukemia enrolled in PETHEMA protocols

Ribera

Morgades

Zamora

et al. 2015

Cancer

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; for the Spanish PETHEMA Group and the Spanish Society of Hematology BACKGROUND: Some copy number alterations (CNAs) have independent prognostic significance for adults with acute lymphoblastic leukemia (ALL). METHODS: This study analyzed via multiplex ligation-dependent probe amplification the frequency and prognostic impact of CNAs of 12 genetic regions in 142 adolescents and adults with de novo precursor B-cell ALL. RESULTS: The cyclindependent kinase inhibitor 2A/B (CDKN2A/B) deletion (59 of 142 or 42%) was the most frequent CNA, and it was followed by Ikaros family zinc finger 1 (IKZF1) losses (49 of 142 or 35%). IKZF1 deletions were more prevalent in Philadelphia chromosome (Ph)-positive ALL and were associated with advanced age and high white blood cell (WBC) counts. The multivariate analysis showed that advanced age and early B-cell factor 1 (EBF1) deletions were associated with chemotherapy resistance in both the whole series (hazard ratios, 0.949 and 0.135, respectively) and the Ph-negative subgroup (hazard ratios, 0.946 and 0.118, respectively). High WBC counts and focal IKZF1 deletions correlated with disease recurrence (hazard ratios, 1.005 and 1.869, respectively), whereas advanced age and CDKN2A/B losses influenced overall survival in both the whole series (hazard ratios, 1.038 and 2.545, respectively) and the Ph-negative subgroup (hazard ratios, 1.044 and 2.105, respectively). CONCLUSIONS: Deletions of EBF1, IKZF1, and CDKN2A/B have an independent adverse prognosis for adolescents and adults with B-precursor ALL, and this suggests that these CNAs should be included in the initial risk assessment of ALL. Cancer 2015;121:3809-17.

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“…7,9,10 In addition, there are case reports of patients responding to TKI treatment indicating that these aberrations represent a promising and relevant therapeutic target especially given the reported unfavorable prognosis of BCR-ABL1-like ALL. [5][6][7][11][12][13][14] However, the biology of this heterogeneous group of abnormalities is not fully understood and there is evidence that the prognosis of patients depends on the type of kinase activating lesion and the presence of cooperating aberrations such as IKZF1 deletions and JAK2 mutations. 7 Further studies, based on patients with specific gene fusions, are therefore warranted.…”

Section: Introductionmentioning

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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Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome

Cited by 363 publications

References 35 publications

The Fat1 cadherin is overexpressed and an independent prognostic factor for survival in paired diagnosis–relapse samples of precursor B-cell acute lymphoblastic leukemia

The Fat1 cadherin is overexpressed and an independent prognostic factor for survival in paired diagnosis–relapse samples of precursor B-cell acute lymphoblastic leukemia

Prognostic significance of copy number alterations in adolescent and adult patients with precursor B acute lymphoblastic leukemia enrolled in PETHEMA protocols

Characterization of leukemias with ETV6-ABL1 fusion

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