B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) Specific Copy Number Alterations Are Unique For Progressive Pediatric Chronic Myeloid Leukemia (CML): A Large Cohort Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2715-2715
Author(s):  
Naomi E van der Sligte ◽  
Manuela Krumbholz ◽  
Agata Pastorczak ◽  
Blanca Scheijen ◽  
Josephine T. Tauer ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
B Cell ◽  
Disease Progression ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Copy Number Alterations ◽  
Cell Precursor ◽  
Predict Disease Progression

Abstract Chronic myeloid leukemia (CML) is a rare malignancy in children and is mostly diagnosed in the chronic phase (CP). In adults, the five-year overall survival rate is 89% for patients on Imatinib and disease progression occurs in 1-3% per year (Druker 2006). Once a blast crisis (BC) has occurred, treatment options are limited with a median survival of only a few months (Cortes 2008). Therefore, early recognition of patients at risk for developing a BC is desirable. Besides the translocation t(9;22)(q34;q11), IKZF1, PAX5, and CDKN2A deletions have been reported in CML lymphoid blast crisis (LyBC) of both adult and pediatric patients (Mullighan 2008, Alpár 2012). The aim of this study was to investigate the presence of IKZF1 deletions and other copy number alterations (CNAs) by MLPA analysis in a large cohort of pediatric CML patients at time of diagnosis in order to determine whether CNAs commonly found in pediatric ALL might predict disease progression and / or treatment response. Between October 1991 and October 2012 a total of 86 children with newly diagnosed CML were included. The median follow up was 31 months. Among the 86 patients, 82 patients were diagnosed in CP, 2 patients in accelerated phase (AP), and 2 patients in LyBC. Six patients experienced progression to a BC respectively a myeloid blast crisis (MyBC) (N=2) and LyBC (N=4). At time of diagnosis, an IKZF1 deletion was detected in one patient diagnosed with CML-AP (Table A, patient no 58). IKZF1 and EBF1 deletions were detected in one patient diagnosed with CML-LyBC (Table A, patient no 22). No CNAs were detected in the 82 patients diagnosed with CML-CP. At time of disease progression, new CNAs were detected at time of the LyBC (Table A, patient no 62, 64, and 67). Due to the absence of material no CNAs could be detected in both patients experiencing a MyBC. In conclusion, we were able to detect CNAs in progressive CML disease (CML-AP and CML-LyBC) and not in the samples at the time of chronic phase in this large pediatric cohort of CML patients. Therefore, the investigated CNAs could not be used to predict disease progression at time of diagnosis. The CNAs detected in patients with progressive CML were similar to specific CNAs detected in pediatric B-cell precursor ALL, indicating a similar disease development (Kuiper 2010). Additionally, our results are in accordance with existing literature, suggesting that mechanisms of disease progression in pediatric and adult CML might be similar (Brazma, 2007). Disclosures: No relevant conflicts of interest to declare.

Centrosome Aberrations in Chronic Myeloid Leukemia (CML) Are Correlated with Disease Progression and Chromosome Instability.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2949-2949
Author(s):  
Michelle Giehl ◽  
Alice Fabarius ◽  
Chun Zheng ◽  
Oliver Frank ◽  
Andreas Hochhaus ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Chromosome Instability ◽  
Chronic Phase ◽  
Normal Karyotype ◽  
Benign Tumors ◽  
Preneoplastic Lesions ◽  
Cd34 Cells

Abstract Purpose: Numerical and structural centrosome abnormalities are hallmarks of a variety of cancers and have been implicated in chromosome missegregation, chromosomal instability, and aneuploidy. These phenomena already occur in preneoplastic lesions like oral leukoplakia, early cervical neoplasias, and small benign tumors of colon and breast. Moreover, deviations from normal karyotype seem to increase as tumors enlarge and become malignant. Genetic instability is a common feature in chronic myeloid leukemia (CML). We sought to establish a relationship between centrosome abnormalities and cytogenetic aberrations in CD34+ cells from CML patients at diagnosis (chronic phase - CP) and in blast crisis (BC). Methods: Diagnosis of CML was established by hematologic, cytogenetic and molecular parameters. Treatment was performed according to the protocols of the German CML study group (www.kompetenznetz-leukaemie.de). CD34+ cells from ten umbilical cord blood specimens served as negative controls. Centrosome number and morphology were analyzed by immunofluorescence microscopy. In brief, CD34+ cells from ficollized peripheral blood samples were concentrated by magnetic cell sorting (MACS) and cytospun onto coated slides. After methanol fixation cells were incubated with antibodies directed to centrosomal proteins Pericentrin and gamma-Tubulin. Antibody-antigen complexes were stained by incubation with FITC- and Cy3-conjugated secondary antibodies. Results: CML CP samples tested at initial diagnosis (n=20) already displayed numerical and structural centrosome aberrations (30.0% +/−2.3) as compared with corresponding normal control cells (n=10) (2.3% +/−1.1). In BC samples (n=10) an increase of centrosome aberrations was observed (58.0% +/−2.0). Conclusion: The findings suggest that centrosome defects in CML occur early and are already present at primary diagnosis. Centrosome defects may contribute to disease progression by generation of further chromosome instability leading to accumulation of alleles carrying pro-oncogenic mutations and loss of alleles containing normal tumor suppressor genes and thus accelerating complex genomic changes associated with CML BC.

Cytogenetic Analysis of 1863 Chineses Patients with Chronic Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4888-4888
Author(s):  
Qitian Mu ◽  
Qiuling Ma ◽  
Yungui Wang ◽  
Xiangmin Tong ◽  
Zhimei Chen ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Newly Diagnosed ◽  
Monocytic Differentiation ◽  
Granulocytic Differentiation ◽  
Monosomy 7

Abstract Abstract 4888 Background: Cytogenetic analyses of chronic myeloid leukemia (CML) have been performed previously in a large number of reports, but systematical research based on large sample sizes is seldom available. In order to further elucidate the cytogenetic nature of CML, we analyzed retrospectively the cytogenetic profiles of 1863 Ph/BCR-ABL-positive CML patients from a research center in China. Results: Of 1266 newly diagnosed CML patients, the median age was 41 years, which is younger than the median age of diagnosis in western populations. The incidence of additional chromosome abnormalities(ACAs) was 3.1% in newly-diagnosed chronic phase(CP), 9.1% in CP after therapy, 35.4% in accelerated phase(AP) and 52.9% in blast phase(BP), reflecting cytogenetic evolution with CML progression. 5.3% patients harbored a variant Ph translocation. A higher prevalence of ACAs was observed in variant Ph translocations than in classical t(9;22) in the disease progression, especially in BP(88.2% vs. 50%, p=0.002). Moreover, a hyperdiploid karyotype and trisomy 8 were closely correlated with myeloid blast crisis(BC) while a hypodiploid karyotype and monosomy 7 were associated with lymphoid-BC. Among subsets of myeloid-BC, compared with myeloid-BC with granulocytic differentiation or monocytic differentiation, myeloid-BC with minimal differentiation had higher ACAs rate (80% vs.46.8%, p=0.009 and 80% vs. 42.9%, p=0.006). Conclusion: CML tends to afflict younger population in China. In the disease progression, the incident of ACAs was higher in variant Ph translocations than in classical t(9;22). Among subsets of myeloid-BC, myeloid with minimal differentiation had distinct cytogenetic features. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Clonal evolution of AML1-ETO coexisting with BCR-ABL and additional chromosome abnormalities in a blastic transformation of chronic myeloid leukemia

2020 ◽  
Vol 48 (5) ◽  
pp. 030006052091923 ◽  
Author(s):  
Cheng-Cheng Ma ◽  
Ye Chai ◽  
Hui ling Chen ◽  
Xin Wang ◽  
Ying Gao ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Chromosomal Abnormalities ◽  
Blast Crisis ◽  
Clonal Evolution ◽  
Molecular Genetic ◽  
Chronic Phase ◽  
Interesting Case

Blast crisis develops in a minority of patients with chronic myeloid leukemia even in the era of tyrosine kinase inhibitor (TKI) therapy. Reports suggest that we know little about the mechanism of BCR-ABL and AML1-ETO co-expression in blast crisis of chronic myeloid leukemia, and that other chromosomal abnormalities also coexist. Here, we document an unusual and interesting case of a 51-year-old female diagnosed in the chronic phase of chronic myeloid leukemia. After undergoing TKI treatment for 3 months, her bone marrow aspirates in the chronic phase had transformed to blast crisis. Molecular genetic testing indicated she was positive for p210 form of BCR-ABL (copy number decreased from 108.91% to 56.96%) and AML1-ETO fusion (copy number, 5.65%) genes and had additional chromosomal abnormalities of t(8; 21)(q22; q22)/t(9; 22)(q34; q11), t(2; 5)(p24; q13) and an additional +8 chromosome.

scholarly journals Analysis of Mechanisms of Blast Crisis in Chronic Myeloid Leukemia By Whole Genome Sequencing

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-19
Author(s):  
Kristina Loy ◽  
Melanie Zenger ◽  
Manja Meggendorfer ◽  
Stephan Hutter ◽  
Wolfgang Kern ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Whole Genome ◽  
Single Mutation ◽  
Resistance Mutations

Background: Thanks to tyrosine kinase inhibitors (TKIs) chronic myeloid leukemia (CML) has become a well manageable disease. This drastically changes once an individual progresses to blast crisis (BC), which carries a poor prognosis. Although progression to BC fortunately is a rare event, the mechanisms leading to transformation from chronic phase to BC are sparsely studied, which led us to perform in depth analyses of CML patients each at diagnosis (D), at molecular or hematological remission (REM) and at BC by whole genome sequencing (WGS). Aim: (1) Study chromosomal and mutational profiles at D, REM and BC (2) Identify chromosomal and molecular genetic mechanisms in progression to BC Patients and Methods: We performed in depth analyses of 11 CML patients with BC confirmed by cytomorphology. REM samples were available for 8 patients, in 1 patient 2 BC samples were sequenced. Median age at D was 59 years (range 31-70) and median time to BC was 2 years (range 0-6). Nine patients received only first line TKI and 2 patients had switched to second- or third line TKIs before or at time of BC. We sequenced DNA of bone marrow (n=17) or peripheral blood (n=14) by WGS at a median coverage of 106x and used Strelka2 for variant calling. Structural variations (SVs) were analyzed by Manta caller, copy number alterations (CNVs) were called using the GATK4 CNV calling pipeline. Results: None of the patients presented with known high risk additional chromosomal aberrations (ACA) at D (Hochhaus et al, Leukemia 2020). Using WGS at D, we found deletions in the breakpoint region of der(9)t(9;22) (n=2), der(22)t(9;22) (n=1) and a translocation involving 12p and der(22)t(9;22) (n=1). Mutations in known myeloid driver genes were found in 4 patients at D. In two patients (DNMT3A, ASXL1) mutations were present at D and BC, while in two patients three ASXL1 mutations were present at D (VAF 27%; 23% and 14%), but could not be detected at BC by WGS and more sensitive targeted sequencing. Both patients presented with complex ACAs detected both by chromosome banding analysis (CBA) and WGS at BC. Other known driver or resistance mutations were not detected in any other sample at D. We identified three mechanisms driving the transition from chronic phase to BC, the first being ABL1 resistance mutations which render one or several TKIs ineffective (n=6/11). All patients developed ABL1 mutations that conferred resistance to the TKI they were receiving. In BC we detected T315I, Y253H, F359V (n=2 each), E450K, Q252H and Q255K (n=1 each) mutations, one patient had T315I, Q255K and F259V mutation combined, all other patients had a single mutation. In one patient two BCs occurred which showed both an additional t(9;10) but differed in the ABL1 mutations: First Q252H was detected and after REM in second BC T315I was present whereas the Q252H was absent. Secondly, in 10/11 of all patients SVs or CNVs were identified in addition to t(9;22)(q34;q11) by WGS in BC. If CBA data was available it confirmed the WGS data. Patients showed an additional t(9;10) (n=1), t(10;11) (n=1), inv(16) (n=1) and CNVs involving virtually all chromosomes which were only detected in BC pointing towards a major role of chromosomal instability. Interestingly WGS detected de-novo leukemic driver mutations in BC that are described primarily in other myeloid malignancies, representing the third mechanism (n=7). Two patients gained truncating mutations in BCOR, one patient each gained a mutation in ASXL1 and CUX1, one patient 3 frameshift mutations in ETV6, another patient two mutations in WT1 and one case gained a CBFB-MYH11 rearrangement which is usually found in a subtype of AML. Conclusion: Using WGS we found three different contributing mechanisms to progression to BC in CML: 1) ABL1 resistance mutations, 2) gain of structural and copy number variations and 3) potentially rise of additional AML like mutations. Since none of these factors were identified at D and REM, a comprehensive screening is recommended to detect, at the earliest possible time point when molecular remission is lost, the drivers to BC and allow early clinical intervention such as allogeneic transplant. Disclosures No relevant conflicts of interest to declare.

Chronic Myeloid Leukemia Stem Cells

Hematology ◽  
2008 ◽  
Vol 2008 (1) ◽  
pp. 436-442 ◽  
Author(s):  
Catriona H. Jamieson
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Targeted Therapy ◽  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Progenitor Cell ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Self Renewal

Abstract Chronic myeloid leukemia (CML) is typified by robust marrow and extramedullary myeloid cell production. In the absence of therapy or sometimes despite it, CML has a propensity to progress from a relatively well tolerated chronic phase to an almost uniformly fatal blast crisis phase. The discovery of the Philadelphia chromosome followed by identification of its BCR-ABL fusion gene product and the resultant constitutively active P210 BCR-ABL tyrosine kinase, prompted the unraveling of the molecular pathogenesis of CML. Ground-breaking research demonstrating that BCR-ABL was necessary and sufficient to initiate chronic phase CML provided the rationale for targeted therapy. However, regardless of greatly reduced mortality rates with BCR-ABL targeted therapy, most patients harbor quiescent CML stem cells that may be a reservoir for disease progression to blast crisis. While the hematopoietic stem cell (HSC) origin of CML was first suggested over 30 years ago, only recently have the HSC and progenitor cell–specific effects of the molecular mutations that drive CML been investigated. This has provided the impetus for investigating the genetic and epigenetic events governing HSC and progenitor cell resistance to therapy and their role in disease progression. Accumulating evidence suggests that the acquired BCR-ABL mutation initiates chronic phase CML and results in aberrant stem cell differentiation and survival. This eventually leads to the production of an expanded progenitor population that aberrantly acquires self-renewal capacity resulting in leukemia stem cell (LSC) generation and blast crisis transformation. Therapeutic recalcitrance of blast crisis CML provides the rationale for targeting the molecular pathways that drive aberrant progenitor differentiation, survival and self-renewal earlier in disease before LSC predominate.

scholarly journals Increase of bcr-abl chimeric mRNA expression in tumor cells of patients with chronic myeloid leukemia precedes disease progression

Blood ◽  
1995 ◽  
Vol 86 (6) ◽  
pp. 2371-2378 ◽  
Author(s):  
A Gaiger ◽  
T Henn ◽  
E Horth ◽  
K Geissler ◽  
G Mitterbauer ◽  
...  
Keyword(s):  
Steady State ◽  
Chronic Myeloid Leukemia ◽  
Mrna Expression ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Leukemic Cells ◽  
Phenotypic Transformation

The translocation t(9;22) in chronic myeloid leukemia (CML) generates a bcr-abl fusion gene that codes for an aberrant chimeric mRNA. Cell lines established from CML patients in blast crisis show higher expression of this aberrant bcr-abl transcript than cells from patients in chronic phase of the disease. This observation provided the stimulus to investigate whether increased expression of the aberrant bcr-abl fusion transcript is critical to the progression of CML from chronic phase to blast crisis. We have monitored the bcr-abl mRNA expression in 25 patients by serial quantitative polymerase chain reaction analyses during a follow-up period of 12 to 156 months after diagnosis, with a median observation time of 28 months. In all patients who have shown disease progression to accelerated phase (n = 4) or blast crisis (n = 7), an increase in bcr-abl mRNA expression was detected up to 16 months before laboratory or clinical parameters showed phenotypic transformation of the malignant clone. To investigate whether the elevated levels of bcr-abl mRNA reflected an increase in the proportion of leukemic cells in the samples analyzed or primarily enhanced transcriptional activity of the bcr-abl fusion gene, we performed quantitative analyses of the bcr-abl gene at the DNA level and of the Ph chromosome at the cytogenetic level and compared these data with steady-state bcr-abl mRNA levels. We show that increased levels of the bcr-abl transcript did not reflect increased proportions of leukemic cells but elevated steady-state levels of the chimeric mRNA in the malignant cells before disease progression. Therefore, our data strongly suggest that an increase of the chimeric mRNA expression in the leukemic cells precedes the phenotypic transformation of the malignant clone.

scholarly journals Integrated Genomic Analysis Identifies ANKRD36 Gene as a Novel and Common Biomarker of Disease Progression in Chronic Myeloid Leukemia

Biology ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1182
Author(s):  
Zafar Iqbal ◽  
Muhammad Absar ◽  
Tanveer Akhtar ◽  
Aamer Aleem ◽  
Abid Jameel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Sanger Sequencing ◽  
Structural Changes ◽  
Kinase Inhibitors ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Genomic Analysis

Background: Chronic myeloid leukemia (CML) is initiated in bone marrow due to chromosomal translocation t(9;22) leading to fusion oncogene BCR-ABL. Targeting BCR-ABL by tyrosine kinase inhibitors (TKIs) has changed fatal CML into an almost curable disease. Despite that, TKIs lose their effectiveness due to disease progression. Unfortunately, the mechanism of CML progression is poorly understood and common biomarkers for CML progression are unavailable. This study was conducted to find novel biomarkers of CML progression by employing whole-exome sequencing (WES). Materials and Methods: WES of accelerated phase (AP) and blast crisis (BC) CML patients was carried out, with chronic-phase CML (CP-CML) patients as control. After DNA library preparation and exome enrichment, clustering and sequencing were carried out using Illumina platforms. Statistical analysis was carried out using SAS/STAT software version 9.4, and R package was employed to find mutations shared exclusively by all AP-/BC-CML patients. Confirmation of mutations was carried out using Sanger sequencing and protein structure modeling using I-TASSER followed by mutant generation and visualization using PyMOL. Results: Three novel genes (ANKRD36, ANKRD36B and PRSS3) were mutated exclusively in all AP-/BC-CML patients. Only ANKRD36 gene mutations (c.1183_1184 delGC and c.1187_1185 dupTT) were confirmed by Sanger sequencing. Protein modeling studies showed that mutations induce structural changes in ANKRD36 protein. Conclusions: Our studies show that ANKRD36 is a potential common biomarker and drug target of early CML progression. ANKRD36 is yet uncharacterized in humans. It has the highest expression in bone marrow, specifically myeloid cells. We recommend carrying out further studies to explore the role of ANKRD36 in the biology and progression of CML.

scholarly journals Integrated Genomic Analysis Identifies ANKRD36 Gene as a Novel and Common Biomarker of Disease Progression in Chronic Myeloid Leukemia

2021 ◽  
Author(s):  
Zafar Iqbal ◽  
Muhammad Absar ◽  
Tanveer Akhtar ◽  
Aamer Aleem ◽  
Abid Jameel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Sanger Sequencing ◽  
Structural Changes ◽  
Kinase Inhibitors ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Genomic Analysis

Background: Chronic Myeloid Leukemia (CML) is initiated in bone marrow due to chromosomal translocation t(22;9) leading to fusion oncogene BCR-ABL. Targeting BCR-ABL by tyrosine kinase inhibitors (TKI) have changed fatal CML into an almost curable disease. Despite that, TKIs lose their effectiveness due to disease progression. Unfortunately, mechanism of CML progression is poorly understood and common biomarkers for CML progression are unavailable. This study was conducted to find out novel biomarkers of CML progression by employing whole exome sequencing (WES).Materials and Methods: WES of accelerated phase (AP-) and blast crisis (BC-) CML patients was carried out, with chronic phase CML (CP-CML) patients as control. After DNA library preparation and exome enrichment, clustering and sequencing was carried out using Illumina platforms. Statistical analysis was carried out using [SAS/STAT] software version 9.4 and R package employed to find mutations shared exclusively by all AP-/BC-CML. Confirmation of mutations was carried out using Sanger sequencing and protein structure modelling using I-Tasser followed by mutant generation and visualization using PyMOL. Results: Three novel genes (ANKRD36, ANKRD36B and PRSS3) were mutated exclusively in all AP-/BC-CML patients. Only ANKRD36 gene mutations (c.1183_1184 delGC and c.1187_1185 dupTT) were confirmed by Sanger sequencing. Protein modelling studies showed that mutations induce structural changes in ANKRD36 protein. Conclusions: Our studies show that ANKRD36 is a potential common biomarker and drug target of early CML progression. ANKRD36 is yet uncharacterized in human. It has the highest expression in bone marrow, specifically myeloid cells. We recommend carrying out further studies to explore the role of ANKRD36 in biology and progression of CML.

scholarly journals ASXL1, TP53 and IKZF3 mutations are present in the chronic phase and blast crisis of chronic myeloid leukemia

2013 ◽  
Vol 3 (11) ◽  
pp. e157-e157 ◽  
Author(s):  
J Menezes ◽  
R N Salgado ◽  
F Acquadro ◽  
G Gómez-López ◽  
M C Carralero ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Chronic Phase
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