Complex rearrangement in acute myeloid leukemia M2 with RUNX1/RUNX1T1 fusion involving chromosomes 8, 17 and 21

Background The translocation t(8;21)(q22;q22) is one of the most frequent chromosomal abnormalities associated with acute myeloid leukemia (AML) sub type M2. About 3–5 % of cases with additional chromosomal abnormalities, including structural and numerical ones, are reported to include a complex translocation t(8;21;N). Case presentation Here we report a chromosome rearrangement observed in a 19 years-old female diagnosed with AML-M2. When subjected to (molecular) cytogenetic analyses a complex three-way translocation involving chromosomes 8, 17 and 21 was detected, forming not a t(8;21;17) as one would expect. Real time-polymerase chain reaction analysis using 6 AML specific markers showed the presence of RUNX1/RUNX1T1 fusion gene transcripts identical to those found in classical translocation t(8;21) coupled with presence of FLT3-ITD mutation identified by fragment analysis. Conclusions The present case highlights importance of complex rearrangements rarely encountered in AML, suggesting that all involved regions harbor critical candidate genes regulating the pathogenesis of AML, leading to novel as well as well-known leukemia associated chromosomal aberrations.

Chromosomal Aberrations in Chronic Myeloid Leukemia: Response to Conventional TKIs and Risk of Blastic Transformation

Background and Purpose: Chronic Myeloid Leukemia (CML) is a common hematological malignancy. The characteristic molecular abnormality is the presence of Philadelphia chromosome or BCR-ABL fusion gene which is the result of 9:22 translocation. Tyrosine kinase inhibitors (TKIs) form the main stay of treatment in CML with excellent responses. The purpose of this study was to determine the impact of additional chromosomal abnormalities on outcomes in CML.Methods: This is a retrospective chart review of all patients who were diagnosed with CML in chronic phase (CP) with additional chromosomal abnormalities (ACAs) over a period of 5 years from 2010 to 2015 at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan. Results: A total of 283 patients were diagnosed with CML from January 2010 to January 2015. 31 patients out of these were found to have additional chromosomal abnormalities at the time of diagnosis in addition to BCR-ABL fusion gene or Philadelphia chromosome detection. Out of these 31 patients, 23 (74.2%) were males whereas 8 (25.8%) were females. 13 (41.9%) were in the age group of 31 to 50 years whereas the other two groups that is 18 to 30 years and 51 to 70 years had 9 patients each. After approval from the government which usually takes a standard 2-3 weeks’ time, these patients were started on tyrosine kinase inhibitors which was Imatinib in 30 (96.8%) and Nilotinib in 1 (3.2%) patient. Conventional cytogenetic analysis performed for each patient at the time of diagnosis revealed that 11 (35.5%) of patients had variant Philadelphia chromosome followed by 7 patients (22.6%) with trisomy 8. 5 patients (16.1%) had multiple chromosomal abnormalities including trisomy 8, deletion 1 and isochrome 17q. 2 patents each had isochrome 17q, inversion 3 and deletion 9 abnormalities. 1 patient had deletion 7 whereas 1 had variant Philadelphia chromosome with other chromosomal abnormalities. Conclusion: It was evident that frequently occurring ACAs In our CML population were Variant Philadelphia chromosome and trisomy 8.

IUGR is Commonly Observed among Prenatally Diagnosed Chromosome 4p Deletion Syndrome

Objective: our study aimed at retrospectively assessing the abnormal prenatal ultrasound findings of chromosome 4p deletion syndrome. Methods: 21 cases with abnormal sonographic signs revealed 4p deletion by Chromosome Microarray (CMA) in this retrospective analysis. Clinical information and molecular basis of this cohort were compared with those from other two groups in China, the critical region related to special ultrasound findings was mapped with the smallest regions of overlap. Results: This is the largest prenatal series to evaluate the prenatal ultrasound features of 4p deletion syndrome detected by CMA. Firstly we refined the relationship between the genomic coordinates with IUGR in chromosome 4p terminal deletion syndrome. Additional chromosomal abnormalities was identified in 12 cases. Intrauterine embryonic arrest was diagnosed at first trimester for 9 cases. The most consistent ultrasound indicator was IUGR (95.5%), and the smallest region response for IUGR correspond to a 2.05Mb at 4p16.3-pter (chr4: 68,345-2,121,057, hg19). Increased Nuchal Translucency (NT) could be a risk factor for predicting WHS at first-trimester pregnancy with the rate of 16.6% from our data. A 3.6Mb microdeletion located at 4p16.3-pter (chr4: 68,345-3,753,422, hg19) might be the candidate region associated with increased NT. Conclusion: We identified IUGR as the most common feature in prenatal 4p terminal deletion and Wolf-Hirschhorn syndrome. The existence of additional CNVs may contribution to possible explanations for the clinical heterogeneity of this syndrome. Prenatal findings of IUGR, increased NT or early spontaneous abortion should warrant the diagnosis of 4p terminal deletion WHS.

Complex rearrangement in acute myeloid leukemia M2 with RUNX1/RUNX1T1 fusion involving chromosomes 8, 17 and 21

BackgroundThe translocation t(8;21)(q22;q22) is one of the most frequent chromosomal abnormalities associated with acute myeloid leukemia (AML) sub type M2. About 3–5% of cases with additional chromosomal abnormalities, including structural and numerical ones, are reported to include a complex translocation t(8;21;N).Case PresentationHere we report a chromosome rearrangement observed in a 19 years-old female diagnosed with AML-M2. When subjected to (molecular) cytogenetic analyses a complex three-way translocation involving chromosomes 8, 17 and 21 was detected, forming not a t(8;21;17) as one would expect. Real time-polymerase chain reaction analysis using 6 AML specific markers showed the presence of RUNX1/RUNX1T1 fusion gene transcripts identical to those found in classical translocation t(8;21) coupled with presence of FLT3-ITD mutation identified by fragment analysis.ConclusionsThe present case highlights importance of complex rearrangements rarely encountered in AML, suggesting that all involved regions harbor critical candidate genes regulating the pathogenesis of AML, leading to novel as well as well-known leukemia associated chromosomal aberrations.

Prognostic impact of Additional Chromosomal Abnormalities in Egyptian Chronic Myeloid Leukemia Patients

BACKGROUND: Emergence of additional chromosomal abnormalities (ACAs) in chronic myeloid leukemia (CML) is associated with disease progression to advanced phases and reflects the genetic instability of CML. AIM: Is to evaluate the frequency of ACAs in chronic phase (CP) and advanced disease (AP) CML patients and study their impact on patient’s outcome, overall survival (OS) and event-free survival (EFS). RESULTS: The studied group (n = 73) included 31 males (43%) and 42 females (57%). Median age of patients at diagnosis was 37 years (17–76). Median TLC was 208×109/L (2.1–784.2), median Hb was 9.4 g/dL (5.7–13), and median platelets count was 290.5×109/L (13–1271). We identified 32 patients (44%) with ACAs. ACAs emergence was significantly associated with advanced phases of CML (13/21, 62%) compared to CP (19/52, 36%) (p = 0.048). ACAs were associated with lower median OS and EFS in CP compared to AP (38 vs. 120 ms) and (58.3 vs. 77 ms) (p = 0.026 and p = 0.065, respectively). Early molecular responders (6/17, 35%) at 3 months, and 6 months (10/26, 38%) developed ACAs less than nonoptimal responders. Disease phase, hepatomegaly and bone marrow eosinophilia were significant predictors of OS (p < 0.001, p = 0.02, p = 0.04, respectively). CONCLUSION: Early identification of ACAs in Ph+ metaphases at diagnosis and during therapy predicts CML outcome. ACAs emergence occurred at a higher frequency and at a younger age in our CML patients and are related to inferior EFS and OS.

Sequencing of RNA in single cells reveals a distinct transcriptome signature of hematopoiesis in GATA2 deficiency

Constitutional GATA2 deficiency caused by heterozygous germline GATA2 mutations has a broad spectrum of clinical phenotypes, including systemic infections, lymphedema, cytopenias, and myeloid neoplasms. Genotype–phenotype correlation is not well understood mechanistically in GATA2 deficiency. We performed whole transcriptome sequencing of single hematopoietic stem and progenitor cells from 8 patients, who had pathogenic GATA2 mutations and myelodysplasia. Mapping patients’ cells onto normal hematopoiesis, we observed deficiency in lymphoid/myeloid progenitors, also evident from highly constrained gene correlations. HSPCs of patients exhibited distinct patterns of gene expression and coexpression compared with counterparts from healthy donors. Distinct lineages showed differently altered transcriptional profiles. Stem cells in patients had dysregulated gene expression related to apoptosis, cell cycle, and quiescence; increased expression of erythroid/megakaryocytic priming genes; and decreased lymphoid priming genes. The prominent deficiency in lympho-myeloid lineages in GATA2 deficiency appeared at least partly due to the expression of aberrant gene programs in stem cells prior to lineage commitment. We computationally imputed cells with chromosomal abnormalities and determined their gene expression; DNA repair genes were downregulated in trisomy 8 cells, potentially rendering these cells vulnerable to second-hit somatic mutations and additional chromosomal abnormalities. Cells with complex cytogenetic abnormalities showed defects in genes related to multilineage differentiation and cell cycle. Single-cell RNA sequencing is powerful in resolving transcriptomes of cell subpopulations despite a paucity of cells in marrow failure. Our study discloses previously uncharacterized transcriptome signatures of stem cells and progenitors in GATA2 deficiency, providing a broad perspective of potential mechanisms by which germline mutations modulate early hematopoiesis in a human disease. This trial was registered at www.clinicaltrials.gov as NCT01905826, NCT01861106, and NCT00001620.

High-risk additional chromosomal abnormalities at low blast counts herald death by CML

Blast crisis is one of the remaining challenges in chronic myeloid leukemia (CML). Whether additional chromosomal abnormalities (ACAs) enable an earlier recognition of imminent blastic proliferation and a timelier change of treatment is unknown. One thousand five hundred and ten imatinib-treated patients with Philadelphia-chromosome-positive (Ph+) CML randomized in CML-study IV were analyzed for ACA/Ph+ and blast increase. By impact on survival, ACAs were grouped into high risk (+8, +Ph, i(17q), +17, +19, +21, 3q26.2, 11q23, −7/7q abnormalities; complex) and low risk (all other). The presence of high- and low-risk ACAs was linked to six cohorts with different blast levels (1%, 5%, 10%, 15%, 20%, and 30%) in a Cox model. One hundred and twenty-three patients displayed ACA/Ph+ (8.1%), 91 were high risk. At low blast levels (1–15%), high-risk ACA showed an increased hazard to die compared to no ACA (ratios: 3.65 in blood; 6.12 in marrow) in contrast to low-risk ACA. No effect was observed at blast levels of 20–30%. Sixty-three patients with high-risk ACA (69%) died (n = 37) or were alive after progression or progression-related transplantation (n = 26). High-risk ACA at low blast counts identify end-phase CML earlier than current diagnostic systems. Mortality was lower with earlier treatment. Cytogenetic monitoring is indicated when signs of progression surface or response to therapy is unsatisfactory.

Additional chromosomal abnormalities in Philadelphia positive chronic myeloid leukemia

Objective: To determine the frequency of additional chromosomal abnormalities in Philadelphia chromosome positive Chronic Myeloid Leukemia (CML) by conventional cytogenetic analysis. Methods: This descriptive cross sectional study was conducted at Armed Forces Institute of Pathology (AFIP), Rawalpindi, from January 2012 to December 2016. A total number of 528 newly diagnosed CML patients were included in the study. The subjects were tested for the presence of Philadelphia (Ph) chromosome and other additional cytogenetic abnormalities by conventional cytogenetic analysis interpreted according to International System of Human Cytogenetic Nomenclature (ISCN) criteria. Molecular analysis for BCR-ABL was also performed for each patient. The additional cytogenetic abnormalities were then classified into major route abnormalities and minor route abnormalities. Results: Out of the 528 newly diagnosed CML patients, 378 (71.6%) were males and 150 (28.4%) were females. The age of patients ranged between 18 to 74 years. Four hundred and ninety-eight (94.3%) patients showed Philadelphia chromosome on karyotyping while 30 (5.7%) were negative for the Philadelphia chromosome. On analysis of these 498 Philadelphia positive patients, additional cytogenetic aberrations were detected in 26 (4.9%) patients. Of these, 7 (1.3%) had major route abnormalities while 19 (3.6%) had minor route abnormalities. Conclusion: The frequency of additional chromosomal abnormalities in our study were not in accordance with previous local and international studies. doi: https://doi.org/10.12669/pjms.36.2.1384 How to cite this:Tashfeen S, Mahmood R, Khan SA, Khadim T. Additional chromosomal abnormalities in Philadelphia positive chronic myeloid leukemia. Pak J Med Sci. 2020;36(2):---------. doi: https://doi.org/10.12669/pjms.36.2.1384 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.