Low Frequency of ETV6-RUNX1 (t 12; 21) in Saudi Arabian Pediatric Acute Lymphoblastic Leukemia Patients: Association with Clinical Parameters and Early Remission

Abstract Abstract : Introduction: t(12; 21) leading to ETV6-RUNX1 fusion oncogene is associated with better prognosis and excellent treatment outcome in pediatric ALL (pALL) patients have good prognosis as compared to other genetic abnormalities1. Accordingly, frequency of ETV6-RUNX1 has a huge implication in treatment strategies of pALL in a given population. Different ethnic groups from various geographical regions have different frequencies of ETV6-RUNX1 ranging from 10% (Southeast Asia) to 33% (Australia) 2,3. Therefore, aim of this study was to determine ETV6-RUNX1 status of Saudi Arabian pALL patients and its association with clinical parameters and early remission. Patients & Methods: Pediatric Acute Lymphoblastic Leukemia (pALL) patients at King Abdulaziz Medical City represent pure Saudi Arabian population. Clinical parameters and ETV6-RUNX1 status (using FISH technique) of pALL patients attending Pediatric Oncology Clinic, King Abdulaziz Medical City Riyadh from 2006 to 2011 were studied using Vysis ETV6/RUNX1 DF FISH Probe Kit (Abbot Laboratories, Illinois, USA)4. CCG1991 protocol was used for standard risk patients while CCG1961 protocol was used for high risk patients. Number of blasts at day 14 and day 29 of the treatment were also calculated as a part of routine clinical follow-up.Comparison between ETV6-RUNX1 positive and negative groups done using chi-square test or Fisher's exact test. All Statistical analysis was performed using SAS version 9.2 (SAS Institute, Inc., Cary, NC). Results: Out of 54 patients, 33 were male and 21 were females (ration1.57:1). B- and T-cell lineage was found in 47 (87%) and 7 (13%) patients respectively. Only 5 (9.3%) patients with ETV6-RUNX1 positive while 49(80.7%) were ETV6-RUNX1 negative. All ETV6-RUNX1 patients (100%) were of B-cell lineage and 80% (4/5) were in 3-7 year age group. None of ETV6-RUNX11 patients had ≥5% blasts (no remission) at Day 14 as compared to 9% patients from ETV6-RUNX1 negative group (Table 1). Discussion: Frequency of ETV6-RUNX1 positive patients (less than 10%) in our pALL patients is much lower than reported in most of the European countries, North America, Australia and Japan while it is in accordance with ETV6-RUNX1 frequencies from Egypt (11.6%), Pakistan (10%), and India (5-7%) 2,3,5,6. This diversity in frequencies of ETV6-RUNX1 among pALL can be attributed to level of industrialization and/or westernized lifestyle. Moreover, ethnic differences in frequencies of this and other prognostically important genetic abnormalities can have a significant bearing on global pediatric ALL management strategies7 which necessitates further large scale studies in this regard. References: 1. Cooper SL, Brown PA. Treatment of pediatric acute lymphoblastic leukemia. Pediatr Clin North Am. 2015 Feb;62(1):61-73. 2. Iqbal Z. Molecular genetic studies on 167 pediatric ALL patients from different areas of Pakistan confirm a low frequency of the favorable prognosis fusion oncogene TEL-AML1 (t 12; 21) in underdeveloped countries of the region. Asian Pac J Cancer Prev. 2014;15(8):3541-6. 3. Amor DJ, Algar EM, Slater HR, Smith PJ. High frequency of t(12;21) in childhood acute lymphoblastic leukemia detected by RT-PCR. Pathology. 1998 Nov;30(4):381-5. 4. Vysis ETV6/RUNX1 DF FISH Probe Kit. https://www.abbottmolecular.com/vysis-etv6runx1-df-fish-probe-kit.html 5. Harbott J, Viehmann S, Borkhardt A, Henze G, Lampert F. Incidence of TEL/AML1 fusion gene analyzed consecutively in children with acute lymphoblastic leukemia in relapse. Blood. 1997 Dec 15;90(12):4933-7. 6. Shurtleff SA, Buijs A, Behm FG, Rubnitz JE, Raimondi SC, Hancock ML, Chan GC, Pui CH, Grosveld G, Downing JR. TEL/AML1 fusion resulting from a cryptic t(12;21)is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis. Leukemia. 1995 Dec;9(12):1985-9. 7. Weso³owska-Andersen A, Borst L, Dalgaard MD, Yadav R, Rasmussen KK, Wehner PS,et al. Genomic profiling of thousands of candidate polymorphisms predicts risk of relapse in 778 Danish and German childhood acute lymphoblastic leukemia patients. Leukemia. 2015 Feb;29(2):297-303. Disclosures Saglio: Novartis: Consultancy, Honoraria; BMS: Consultancy.

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Improving brain function of pediatric acute lymphoblastic leukemia patients after induction chemotherapy, a pilot self-contrast study by fractional amplitude of low-frequency fluctuation

Journal of Clinical Neuroscience ◽

10.1016/j.jocn.2019.04.033 ◽

2019 ◽

Vol 66 ◽

pp. 149-155

Author(s):

Dongfang Zou ◽

Feiqiu Wen ◽

Hongwu Zeng ◽

Huirong Mai ◽

Xiuli Yuan ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Induction Chemotherapy ◽

Brain Function ◽

Lymphoblastic Leukemia ◽

Low Frequency ◽

Frequency Fluctuation ◽

Contrast Study ◽

Pediatric Acute Lymphoblastic Leukemia

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Faculty Opinions recommendation of Epigenetics in pediatric acute lymphoblastic leukemia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.731120594.793548064 ◽

2018 ◽

Author(s):

Kenneth Ramos

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Pediatric Acute Lymphoblastic Leukemia

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Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia

Scientific Reports ◽

10.1038/s41598-021-95109-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shumaila Sayyab ◽

Anders Lundmark ◽

Malin Larsson ◽

Markus Ringnér ◽

Sara Nystedt ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Large Scale ◽

Somatic Mutations ◽

Lymphoblastic Leukemia ◽

Clonal Evolution ◽

Point Mutations ◽

Driver Genes ◽

Protein Coding ◽

Pediatric Acute Lymphoblastic Leukemia ◽

Evolutionary Trajectories

AbstractThe mechanisms driving clonal heterogeneity and evolution in relapsed pediatric acute lymphoblastic leukemia (ALL) are not fully understood. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients. Somatic point mutations and large-scale structural variants were called using individually matched remission samples as controls, and allelic expression of the mutations was assessed in ALL cells using RNA-sequencing. We observed an increased burden of somatic mutations at relapse, compared to diagnosis, and at second relapse compared to first relapse. In addition to 29 known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, we identified putative non-protein coding mutations in regulatory regions of seven additional genes that have not previously been described in ALL. Cluster analysis of hundreds of somatic mutations per sample revealed three distinct evolutionary trajectories during ALL progression from diagnosis to relapse. The evolutionary trajectories provide insight into the mutational mechanisms leading relapse in ALL and could offer biomarkers for improved risk prediction in individual patients.

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Pediatric acute lymphoblastic leukemia complicated by secondary hemophagocytic lymphohistiocytosis

Pediatric Blood & Cancer ◽

10.1002/pbc.22064 ◽

2009 ◽

Vol 53 (3) ◽

pp. 491-492 ◽

Cited By ~ 14

Author(s):

Omer Devecioglu ◽

Sema Anak ◽

Didem Atay ◽

Pinar Aktan ◽

Esra Devecioglu ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Hemophagocytic Lymphohistiocytosis ◽

Lymphoblastic Leukemia ◽

Pediatric Acute Lymphoblastic Leukemia ◽

Secondary Hemophagocytic Lymphohistiocytosis

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Advances in the Diagnosis and Treatment of Pediatric Acute Lymphoblastic Leukemia

Journal of Clinical Medicine ◽

10.3390/jcm10091926 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1926

Author(s):

Hiroto Inaba ◽

Ching-Hon Pui

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Detailed Analysis ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Survival Rates ◽

Treatment Strategies ◽

Chemotherapeutic Agents ◽

Response To Treatment ◽

Pediatric Acute Lymphoblastic Leukemia ◽

Therapeutic Implications

The outcomes of pediatric acute lymphoblastic leukemia (ALL) have improved remarkably during the last five decades. Such improvements were made possible by the incorporation of new diagnostic technologies, the effective administration of conventional chemotherapeutic agents, and the provision of better supportive care. With the 5-year survival rates now exceeding 90% in high-income countries, the goal for the next decade is to improve survival further toward 100% and to minimize treatment-related adverse effects. Based on genome-wide analyses, especially RNA-sequencing analyses, ALL can be classified into more than 20 B-lineage subtypes and more than 10 T-lineage subtypes with prognostic and therapeutic implications. Response to treatment is another critical prognostic factor, and detailed analysis of minimal residual disease can detect levels as low as one ALL cell among 1 million total cells. Such detailed analysis can facilitate the rational use of molecular targeted therapy and immunotherapy, which have emerged as new treatment strategies that can replace or reduce the use of conventional chemotherapy.

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Unravelling the Sequential Interplay of Mutational Mechanisms during Clonal Evolution in Relapsed Pediatric Acute Lymphoblastic Leukemia

Genes ◽

10.3390/genes12020214 ◽

2021 ◽

Vol 12 (2) ◽

pp. 214

Author(s):

Željko Antić ◽

Stefan H. Lelieveld ◽

Cédric G. van der Ham ◽

Edwin Sonneveld ◽

Peter M. Hoogerbrugge ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

De Novo ◽

Lymphoblastic Leukemia ◽

Clonal Evolution ◽

Leukemic Cells ◽

Proliferative Potential ◽

Disease Evolution ◽

Pediatric Acute Lymphoblastic Leukemia ◽

First Relapse ◽

Mutational Processes

Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and is characterized by clonal heterogeneity. Genomic mutations can increase proliferative potential of leukemic cells and cause treatment resistance. However, mechanisms driving mutagenesis and clonal diversification in ALL are not fully understood. In this proof of principle study, we performed whole genome sequencing of two cases with multiple relapses in order to investigate whether groups of mutations separated in time show distinct mutational signatures. Based on mutation allele frequencies at diagnosis and subsequent relapses, we clustered mutations into groups and performed cluster-specific mutational profile analysis and de novo signature extraction. In patient 1, who experienced two relapses, the analysis unraveled a continuous interplay of aberrant activation induced cytidine deaminase (AID)/apolipoprotein B editing complex (APOBEC) activity. The associated signatures SBS2 and SBS13 were present already at diagnosis, and although emerging mutations were lost in later relapses, the process remained active throughout disease evolution. Patient 2 had three relapses. We identified episodic mutational processes at diagnosis and first relapse leading to mutations resembling ultraviolet light-driven DNA damage, and thiopurine-associated damage at first relapse. In conclusion, our data shows that investigation of mutational processes in clusters separated in time may aid in understanding the mutational mechanisms and discovery of underlying causes.

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