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Blast morphology in CML with 11q23, blast phase. (A) A case of acute leukemia without maturation (case 8). (B) A case of acute leukemia with monocytic differentiation (case 7) (NSE: non-specific esterase).
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Background
Progression of chronic myelogenous leukemia (CML) is frequently accompanied by cytogenetic evolution, commonly unbalanced chromosomal changes, such as an extra copy of Philadelphia chromosome (Ph), +8, and i(17)(q10). Balanced chromosomal translocations typically found in de novo acute myeloid leukemia occur occasionally in CML, such as...
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The introduction of highly selective ABL-tyrosine kinase inhibitors (TKIs) has revolutionized therapy for chronic myeloid leukemia (CML). However, TKIs are only efficacious in the chronic phase of the disease and effective therapies for TKI-refractory CML, or after progression to blast crisis (BC), are lacking. Whereas the chronic phase of CML is d...
Citations
... In the current study, patients with ACAs had a significantly higher blast count and more advanced stages. These findings are completely consistent with previous research [19,20]. In 2019, a study by Chandran and his colleagues came to a similar conclusion when they reported a considerably greater incidence of ACAs in patients diagnosed with BP and accelerated phase (AP) of CML [4]. ...
Background
Chronic myeloid leukaemia is characterised by genetic instability which results in additional cytogenetic aberrations that have been linked to progression to advanced phase. Genomic study linked amplified genes in the form of c-MYC and/or the rare BCR::ABL1 genes amplification to chronic myeloid leukaemia. The effect of these genes’ amplification on patients’ characteristics and disease progression still needs further study.
This cross-sectional study aimed to investigate the frequency of additional chromosomal aberrations in addition to c-MYC and BCR::ABL 1 genes amplification in chronic myeloid leukaemia patients and their impact on patient’s characteristics, disease progression, and level of remission. The study included cytogenetic analysis of 49 Philadelphia positive chronic myeloid leukaemia patients and investigation of c-MYC and BCR::ABL1 genes amplification by fluorescence in situ hybridization.
Results
Patients with additional chromosomal aberrations represented 36.7% and had significantly lower platelet count ( P = 0.003) and higher blast count ( P = 0.008). The acquisition of additional chromosomal aberrations was significantly higher in chronic myeloid leukaemia patients with advanced stages ( P = 0.014). Follow-up of the patients for 6 months revealed significant higher frequency of additional chromosomal aberrations in patients with failure of remission ( P < 0.0001). A highly significant association between cases with failure of molecular remission ( P = 0.001) and co-existing additional chromosomal aberrations.
Amplification of the c-MYC gene was detected in 6 cases. The cases with c-MYC amplification showed significantly higher peripheral blood and bone marrow blasts ( P = 0.029 and P = 0.008, respectively) and significantly lower platelet count ( P = 0.044). Amplification of c-MYC was significantly associated with additional chromosomal aberrations ( P = 0.011). Molecular remission was not achieved in any of the instances with c-MYC amplification. A highly significant association between c-MYC amplification and poor patient outcome was detected ( P = 0.002). BCR::ABL1 amplification was detected in three cases, and ABL amplification was detected in four cases. Patients with BCR::ABL1 amplification showed significantly higher blast count. BCR::ABL1 amplification was significantly associated with disease progression and failure of molecular remission ( P = 0.002).
Conclusion
Additional chromosomal aberrations, c-MYC amplification, and BCR:ABL1 amplification in chronic myeloid leukaemia stratify patients with disease progression, which may lead to better interventions and improved outcome in the future chronic myeloid leukaemia patients.
... While the BCR::ABL1 fusion gene is a well-known hallmark of CML, other concurrent gene fusions have also been described. Cytogenetic studies reported several translocations in CML, including those involving RUNX1, MECOM, and MLL (KMT2A) [34,[46][47][48][49]. Furthermore, recent RNAseq studies have provided a more comprehensive view of gene fusion in CML patients. ...
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the BCR::ABL1 fusion gene, which aberrantly activates ABL1 kinase and promotes the overproduction of leukemic cells. CML typically develops in the chronic phase (CP) and progresses to a blast crisis (BC) after years without effective treatment. Although prognosis has substantially improved after the development of tyrosine kinase inhibitors (TKIs) targeting the BCR::ABL1 oncoprotein, some patients still experience TKI resistance and poor prognosis. One of the mechanisms of TKI resistance is ABL1 kinase domain mutations, which are found in approximately half of the cases, newly acquired during treatment. Moreover, genetic studies have revealed that CML patients carry additional mutations that are also observed in other myeloid neoplasms. ASXL1 mutations are often found in both CP and BC, whereas other mutations, such as those in RUNX1, IKZF1, and TP53, are preferentially found in BC. The presence of additional mutations, such as ASXL1 mutations, is a potential biomarker for predicting therapeutic efficacy. The mechanisms by which these additional mutations affect disease subtypes, drug resistance, and prognosis need to be elucidated. In this review, we have summarized and discussed the landscape and clinical impact of genetic abnormalities in CML.
... Chromosome i(17)(q10) abnormality is described as any unreasonable damage or breakage of the centromeres of chromosome 17, resulting in absence of the short arm and an iso-arm of the long arm [1]. Isochromosome 17 i(17)(q10) is mainly associated with chronic myeloid leukemia (CML) [2,3], myelodysplastic syndrome/myeloproliferative tumors (MDS/MPD) [4][5][6], and acute myeloid leukemia (AML) [6,7]. Genetic mutation analysis showed that 95% of patients with chromosome karyotype i(17)(q10) carried at least one mutation, and on average three mutations. ...
... Further clinical follow-up is required, and hematopoietic stem cell transplantation is necessary. However, this case was different from occult APL and APL with i(17)(q10) and PML-RARa fusion gene, for which the ATRA and As 2 O 3 combined chemotherapy was effective [2,18]. ...
Background:
Chromosome i(17)(q10) abnormality is mainly associated with chronic myeloid leukemia (CML), myelodysplastic syndrome/myeloproliferative tumors (MDS/MPD), and acute myeloid leukemia (AML). The role of i(17)(q10) in AML is still unknown, the differences between AML and acute promyelocytic leukemia (APL)-like AML with i(17)(q10) need more research. This study aimed to investigate the clinical characteristics and laboratory evidence of 2 AML cases with i(17)(q10), similar to APL phenotype.
Case summary:
Both pediatric patients were males; case 1 had newly diagnosed AML, and case 2 showed relapsed tumor after 1 year of drug withdrawal. Bone marrow cell morphology, chromosome karyotype analysis, Fully-instrumented submersible housing test, immunological assays, molecular biological methods, and blood tumor panoramic gene test were performed. All-trans retinoic acid (ATRA) combined with arsenic acid (As2O3) were used in the first course of treatment. Bone marrow was dominated by abnormal promyelocytic granulocytes. Karyotype test revealed i(17)(q10) isochromosome. Immunological phenotype mainly included positive expressions of CD9, CD13, CD33, and CD38. Case 1 suffered intracranial hemorrhage after re-chemotherapy and died on D162. For case 2, on D145 and D265, bone marrow promyelocytic granulocytes accounted for 2%. Flow cytometric residual lesion detection showed no abnormal immunophenotype cells. The copy number of WT1 gene in two cases were 1087 and 1010, respectively, and the expression rates were 55.29% and 59.5%, respectively.
Conclusion:
ATRA, As2O3, and chemotherapy may be ineffective in treating APL-like AML with i(17)(q10) but without t(15;17) and PML-RARA fusion gene.
... About 1% of patients gain a translocation t(3;21)(q26;q22) in addition to t(9;22) and this is usually a sign of transformation into BC although the t(3;21) can also be found in CML prior to the onset of BC [48,49,[53][54][55]. Likewise, the AML-typical aberrations like t(15;17)(q24;q21) with PML-RARA fusion transcript, inv(3)(q21q26)/t(3;3)(q21;q26) involving the MECOM locus, t(7;11)(p15;p15) with NUP98-HOXA9, t(8;21)(q22;q22) with RUNX1-RUNX1T1, rearrangements involving the KMT2A gene at 11q23, and inv (16)(p13q22) with CBFB-MYH11 can occur during disease progression [22,54,[56][57][58][59][60][61][62]. These AML-specific aberrations can be seen as a warning sign and they have been related to quite specific phenotypic features. ...
Telling the story of the advances in chronic myeloid leukemia (CML), seen from a historical perspective, one cannot deny the extraordinary role of cytogenetics. When John Hughes Bennett and Rudolf Virchow reported what is thought to be the first descriptions of CML in 1845, nothing was known about the mechanism and the underlying genetics. Therefore, it was a quantum leap when the Philadelphia chromosome was discovered by Peter Nowel and David Hungerford in 1960 [1, 2]. By that time, they still used very basic chromosome staining techniques. The cells were grown on slides using short-term cell cultures [3], rinsed with tap water, and stained with Giemsa [4, 5]. Investigating acute leukemia they initially did not find consistent genetic abnormalities, but eventually they identified a characteristic small chromosome in two patients with CML. Together with other scientists like Paul Moorhead they were able to improve their preparation technique and report a series of seven patients all displaying a minute chromosome. In accordance with the Committee for the Standardization of Chromosomes, Tough and colleagues called this minute chromosome Philadelphia chromosome after the city it was first detected [4]. As cytogenetic techniques improved in the 1970s, Rowley discovered that the Philadelphia chromosome is the result of a translocation t(9;22)(q34;q11) between the long arms of chromosomes 9 and 22 with the derivative chromosome 22, der(22)t(9;22), being the Philadelphia chromosome [6]. de Klein et al. were then able to demonstrate that a small segment of chromosome 9 was translocated back to chromosome 22, providing evidence for the reciprocal nature of the translocation t(9;22) [7]. Later, Bartram and co-workers could show that the tyrosine kinase gene ABL1 (abelson) on chromosome 9 and the BCR (breakpoint cluster region) gene on chromosome 22 are fused and generate the BCR-ABL1 fusion gene on the Philadelphia chromosome [8–10]. This was the basis for the characterization of the BCR-ABL1 fusion protein, the development of the first BCR-ABL1 tyrosine kinase inhibitor (TKI) imatinib in 1996 and the success story of CML treatment [11–13]. Currently, the life expectancy of patients with newly diagnosed CML in chronic phase (CP) is very close to that of age-matched individuals [14, 15].
... Fusion genes represent another class of somatic mutations that have an established driver role in leukemia [88]. Early cytogenetic studies described translocations, including cryptic translocations, that resulted in fusion genes involving known leukemiaassociated genes, including CBFB-MYH11 [89], as well as RUNX1 [39,[90][91][92][93] and MLL [94] fusions with various partners. RNA sequencing is a powerful tool for identifying clinically relevant fusion genes [52,95]. ...
The BCR-ABL1 fusion gene, which causes aberrant kinase activity and uncontrolled cell proliferation, is the hallmark of chronic myeloid leukemia (CML). The development of tyrosine kinase inhibitors (TKI) that target the BCR-ABL oncoprotein has led to dramatic improvement in CML management. However, some challenges remain to be addressed in the TKI era, including patient stratification and the selection of frontline TKIs and CML progression. Additionally, with the emerging goal of treatment-free remission (TFR) in CML management, biomarkers that predict the outcomes of stopping TKI remain to be identified. Notably, recent reports have revealed the power of genome screening in understanding the role of genome aberrations other than BCR-ABL1 in CML pathogenesis. These studies have discovered the presence of disease-phase specific mutations and linked certain mutations to inferior responses to TKI treatment and CML progression. A personalized approach that incorporates genetic data in tailoring treatment strategies has been successfully implemented in acute leukemia, and it represents a promising approach for the management of high-risk CML patients. In this article, we will review current knowledge about the mutational profile in different phases of CML as well as patterns of mutational dynamics in patients having different outcomes. We highlight the effects of somatic mutations involving certain genes (e.g. epigenetic modifiers) on the outcomes of TKI treatment. We also discuss the potential value of incorporating genetic data in treatment decisions and the routine care of CML patients as a future direction for optimizing CML management.
... The prognostic significance of ACA/Ph 1 is related to the specific chromosomal abnormality and other features of accelerated phase. [37][38][39][40][41] The presence of "major route" ACA/Ph 1 (trisomy 8, isochromosome 17q, second Ph, and trisomy 19) at diagnosis may have a negative prognostic impact on survival and disease progression to accelerated or blast phase. [42][43][44] However, in a more recent analysis that evaluated the outcomes of patients with CP-CML (with or without ACA) treated with TKI therapy in prospective studies, the presence of ACA/Ph 1 at the time of diagnosis was not associated with worse prognosis. ...
Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase CML.
... One case of t(9; 22) accompanied by t(3;21) was reported in 2006 [10]. 11q23 rearrangements in chronic myelogenous leukemia are extremely rare, accounting for less than 1% of cases reported in the literature to date [11]. CML with the t(9;22) translocation rarely incurs the additional t(9; 11) during disease progression. ...
Abstract Progression of chronic myelogenous leukemia (CML) is frequently accompanied by cytogenetic evolution. Additional genetic abnormalities are seen in 10–20% of CML cases at the time of diagnosis, and in 60–80% of cases of advanced disease. Unbalanced chromosomal changes such as an extra copy of the Philadelphia chromosome (Ph), trisomy 8, and i(17)(q10) are common. Balanced chromosomal translocations, such as t(3;3), t(8;21), t(15;17), and inv(16) are typically found in acute myeloid leukemia, but rarely occur in CML. Translocations involving 11q23, t(8;21), and inv(16) are relatively common genetic abnormalities in acute leukemia, but are extremely rare in CML. In the literature to date, there are at least 76 Ph+ cases with t(3;21), 47 Ph+ cases with inv(16), 16 Ph+ cases with t(8;21), and 9 Ph+ cases with t(9;11). But most of what has been published is now over 30 years old, without the benefit of modern immunophenotyping to confirm diagnosis, and before the introduction of treatment regimes such as TKI. In this study, we explored the rare concomitant occurrence of coexistence current chromosomal translocation and t(9;22) in CML or acute myeloid leukemia (AML).
... Majorroute ACAs have been associated with shorter survival, if they were detected at diagnosis [16] or if they emerged in the course of disease [17]. A poor prognosis was also observed with 3q26.2 and 11q23 rearrangements and with −7/7q− [18,19], whereas +8 and +Ph as single aberrations, but not in combination, were not equally associated with poor prognosis [20]. Wang et al. [17] proposed a risk stratification of the six most frequent ACAs into two groups with distinct prognoses (+8, +Ph, −Y with good prognoses and i[17q], −7/7q−, 3q26.2 rearrangements with poor prognoses). ...
... Complex karyotypes were defined as three or more concurrent aberrations. High-risk ACAs were defined as the major route ACA +8, +Ph, i[17q], +19, +21, +17 (the ACA most frequently observed in BC) [1], the minor route ACA 3q26.2, 11q23, −7/7q− (less frequently observed, but negative impact on prognosis) [17,19,18], and complex karyotypes. Variant translocations and −Y were not considered, as they had no impact on prognosis in our and other studies [16,26]. ...
... Impact of +Ph on survival was equally poor whether it occurred alone or in combination with other abnormalities (Fig. 2b). Chromosome 3,7,17,19, and 21 aberrations were grouped together, as they were rare (Fig. 2d). Individual analyses of these aberrations are shown in Fig. 2e-i. ...
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.
... Genomic alterations, particularly aberrant chromosomal translocations, are responsible for the onset of many types of cancers 1,2 , such as leukemia. For example, PML-RARα (t15; t17) 3,4 , MLL fusions (t11) [5][6][7] , and AML1-ETO (t8; t21) [8][9][10] are typical oncogenic fusion genes that contribute to particular subtypes of leukemogenesis. How these rearrangements can lead to tumorigenesis has traditionally been explained by their ability to encode and express proteins; such proteins are commonly referred to as oncogenic 'fusion proteins' 2,11 , indicating that the regulation of mRNA export of fusion proteins is important for oncogenic protein expression. ...
Aberrant chromosomal translocations leading to tumorigenesis have been ascribed to the heterogeneously oncogenic functions. However, how fusion transcripts exporting remains to be declared. Here, we showed that the nuclear speckle-specific long noncoding RNA MALAT1 controls chimeric mRNA export processes and regulates myeloid progenitor cell differentiation in malignant hematopoiesis. We demonstrated that MALAT1 regulates chimeric mRNAs export in an m6A-dependent manner and thus controls hematopoietic cell differentiation. Specifically, reducing MALAT1 or m6A methyltransferases and the ‘reader’ YTHDC1 result in the universal retention of distinct oncogenic gene mRNAs in nucleus. Mechanically, MALAT1 hijacks both the chimeric mRNAs and fusion proteins in nuclear speckles during chromosomal translocations and mediates the colocalization of oncogenic fusion proteins with METTL14. MALAT1 and fusion protein complexes serve as a functional loading bridge for the interaction of chimeric mRNA and METTL14. This study demonstrated a universal mechanism of chimeric mRNA transport that involves lncRNA-fusion protein-m6A autoregulatory loop for controlling myeloid cell differentiation. Targeting the lncRNA-triggered autoregulatory loop to disrupt chimeric mRNA transport might represent a new common paradigm for treating blood malignancies.
... 11q23 rearrangements in chronic myelogenous leukemia are extremely rare, accounting for less than 1% of cases reported in the literature to date [11]. CML with the t(9;22) translocation rarely incurs the additional t(9;11) during disease progression. ...
Progression of chronic myelogenous leukemia (CML) is frequently accompanied by cytogenetic evolution. Additional genetic abnormalities are seen in 10-20 % of CML cases at the time of diagnosis, and in 60–80 % of cases of advanced disease. Unbalanced chromosomal changes such as an extra copy of the Philadelphia chromosome (Ph), trisomy 8, and i(17)(q10) are common. Balanced chromosomal translocations, such as t(3;3), t(8;21), t(15;17), and inv(16) are typically found in acute myeloid leukemia, but rarely occur in CML. Translocations involving 11q23, t(8;21), and inv(16) are relatively common genetic abnormalities in acute leukemia, but are extremely rare in CML. In the literature to date, there are at least 76 Ph+ cases with t(3;21), 47 Ph+ cases with inv(16), 16 Ph+ cases with t(8;21), and 9 Ph+ cases with t(9;11). But most of what has been published is now over thirty years old, without the benefit of modern immunophenotyping to confirm diagnosis, and before the introduction of treatment regimes such as TKI. In this study, we explored the rare concomitant occurrence of coexistence current chromosomal translocation and t(9;22) in CML or acute myeloid leukemia (AML).
