Journal of Cancer Prevention 2017; 22(2): 74-81
Published online June 30, 2017
© Korean Society of Cancer Prevention
Aliasghar Keramatinia1, Alireza Ahadi1,2, Mohammad Esmaeil Akbari1, Maryam Mohseny3, Alireza Mosavi Jarahi3, Narjes Mehrvar1, Neda Mansouri1,2, S.A. Mortazavi Tabatabaei4, and Abolfazl Movafagh1,2
1Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran, 2Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran, 3Department of Social Medicine, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran, 4Proteomics Research Center, School of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Correspondence to :
Abolfazl Movafagh, Department of Medical Genetics, School of Medicine, Cancer Research Center, Shohada Referral Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran, Tel: +98-21-2240067, E-mail: email@example.com
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Chronic myeloid leukemia (CML) is a hematological stem cell cancer driven by BCR-ABL1 fusion protein. We review the previous and recent evidence on the significance of CML in diagnostic and clinic management. The technical monitoring of
Keywords: Chronic myeloid leukemia, Profile, Methods,
Chronic myeloid leukemia (CML) has been considered as one of the essential neoplastic aberration directly linked to a genetic disorder. CML is a three-phase disease. Most of the patients diagnosed with CML are in a chronic phase (CP) with < 10% myeloblasts in the bone marrow (BM) and blood. Untreated CML-CP invariably transforms into blastic phase (BP) resembling acute myeloid and lymphoid leukemia with > 20% myeloblasts in the bone marrow and peripheral blood. Intermediate phase, named accelerated phase, is defined with 10% to 20% myeloblasts.1 The karyotype mark of CML is Philadelphia (Ph1) chromosome,2 which is a result of chromosomal rearrangement, t(9:22) (q34:q11).3 Aberrant BCR-ABL1 fusion protein constitutively activates downstream enzymes which enhance growth factor-independent proliferation, reprogramed adhesion, and resistance to DNA repair. The transcription of
The tyrosine kinase activated by fusion changes the levels of enzyme phosphorylation and inhibits cellular apoptosis, which are essential for initiating malignancy. TKI effectively inhibits the activity of the BCR-ABL1 proteins in patients with CML by attaching to the ATP-binding pocket of tyrosine kinase5 and managing minimal residual disease and target relapse after curing.6 Responses to TKI therapy are determined with changes in BCR-ABL fusion protein.
The detection of
Cytogenetic method shows metaphase stage by banding methods that subdivide each interphase into many of alternating white and black bands.8 The bone marrow specimen from individual was cultured to obtain metaphase in the slide. After specific staining procedure (e.g., Giemsa, quinacrine mustard), the arrangement of metaphases can be visualized with a fluorescence microscope.
Fluorescence in situ hybridization (FISH) can detect cells in metaphase or interphase, and specimens can derive from bone marrow, peripheral blood, and other specimen. These probes are fluorochrome-labeled and the detected signals are observed with a fluorescence microscope.9 Normally, there is red
The National Comprehensive Cancer Network (NCCN) (Table 1) has provided and updated guidelines for the frequencies of molecular monitoring in patients treated with TKIs.
PCR is used widely to measure
Some mutations in the genes of epigenetic regulators, ASXL1, TET2, TET3, KDM1A, and MSH6 were found in 25% of patients. DNA methylation has reported to be associated with pathogenesis of CML.9 Three loss-of-function mutations (frameshift insertion, deletion, or nonsense mutation) found in
ASXL1 has well-known functions in histone modification and plays a role as a putative tumor suppressor that is often reported to be mutated in hematological malignancies. In myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) patients,
TET2 initiates DNA demethylation and is frequently mutated in hematological malignancies, including CML.16
MSH6 is an essential component of the DNA mismatch repair mechanism.18 Loss-of-function mutation was reported in relapsed ALL patients and the mutation leads to constitutional mismatch repair deficiency syndrome, which is characterized by the development of childhood cancers (Table 2), mainly hematological malignancies.19 Taken together, epigenetic regulation may play important roles against the etiology of CML.
Recurrent somatic mutations in
For molecular testing results to become practical information that affects management decisions, it is imperative to standardize quantitative real time PCR (RT-qPCR) to permit comparison of individual laboratory results to the IRIS data and to enable clinical practice to follow NCCN guidelines.5 RT-qPCR is a technically challenging multistep technique (Fig. 2). Differences in sample collection, cell preparation, RNA isolation, reverse transcription, internal control selection, standard curve construction, and data reporting contribute to the outstanding variation found in the reported
There is predominance of the granulocytic lineage, with dysgranulopoiesis as a defining feature of the disease. However, the presence of eosinophilia in the absence of
No specific cytogenetic alterations have been identified in chromosome banding analysis of patients with CML. There has been an explosion in the discovery of several novel molecular abnormalities in patients with CMML. These can be divided into the following categories: (a) mutations in epigenetic control of transcription,15,21–25 such as histone modification (EZH2, ASXL1, and UTX), DNA methylation (TET2 and DNMT3A), or both (IDH1 and IDH2), (b) mutations in the spliceosome machinery (SF3B1, SRSF2, U2AF35 and U2AF65), (c) mutations in genes that regulate cytokine signaling (
The transition from the chronic to the advanced phase of CML involves distinct changes in gene expression that predict increased activation of the WNT/β-catenin pathway, as well as deregulated expression of several transcriptional regulators, including JunB, Fos, and PRAME.18 Imatinib treatment has clearly improved the prognosis for CML patients, especially in the CP, the occurrence of relapse,1,2 resistance,23,33,34 and the requirement for continued therapy.35,36 Here, we examine the stem cell origin of CML, and then discuss the recent findings that the Hedgehog (Hh) pathway contributes to the survival and expansion of
The Hh pathway, first discovered in the model organism Drosophila, functions in tissue patterning during embryonic development. In the absence of Hh ligands, the Patched (PTCH) receptor functions as an antagonist of the pathway by inhibiting the activation of Smoothened (SMO) (Fig. 3). However, when Hh ligands bind PTCH, this effectively relieves repression on SMO, resulting in its activation. SMO activation culminates in a signal transduction cascade that causes the nuclear translocation of the GLI family of transcription factors (GLI1, 2, 3) and the subsequent induction of a distinct transcriptional regulatory program.
The role of the Hh pathway in post-natal hematopoeisis has been investigated using several experimental approaches. The expression of the two classical Hh target genes,
The molecular mechanisms underlying cancer progression are still uncertain, but most likely involve activation of oncogenic factors and/or inactivation of tumor suppressors.39 A plausible assumption is that BP is a multistep and time-dependent process initiated by both BCR-ABL1–dependent (Fig. 4) and –independent DNA damage associated with inefficient and unfaithful DNA repair in CML-CP. CML-CP, if facilitated by an increased level of BCR-ABL1 activity, leads to selection of one or more CML-BP clones.
The relatively high BCR-ABL1 expression/activity in CML-CP CD34+CD38− stem cells and/or CD34+ early progenitors compared with more committed progenitors, which is further markedly increased in CML-BP CD34+ progenitors, results in the following: enhancement of proliferation/survival pathways, increased genomic instability, activation of pathways blocking in myeloid differentiation, acquisition of the ability for self-renewing, and inhibition of tumor suppressors with broad cell regulatory functions.
The genetic lesions observed in CML-BP patients in the past and now since the introduction of TKIs mostly include the presence of additional chromosomes, gene deletions, gene insertions, and/or point mutations (including
There has been an increased understanding of several key genetic changes that drive CML. In this review, we described and critically evaluated different technologies used to detect
NCCN guidelines on chronic myelogenous leukemia.
|At diagnosis before therapy||RT-qPCR and BM cytogenetics|
|If BM is not feasible, FISH on PB is acceptable|
|During therapy||RT-qPCR||Every 3 months|
|BM cytogenetics||BM cytogenetics At 3, 12, and 18 months|
|After complete cytogenetic response||ABL kinase domain mutation analysis||When initial response is inadequate|
|RT-qPCR||Every 3–6 months|
|BM cytogenetics to detect clonal evolution||As clinically indicated|
|FISH is not recommended|
|Increasing levels of ||Evaluate compliance||As clinically indicated|
|Repeat RT-qPCR in those with MMR|
|BM cytogenetics in those without MMR|
|Consider ABL kinase domain mutation analysis|
National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines) Chronic Myelogenous Leukemia version 3.2013 (section CML-A, page 15; http://www.nccn.org/professionals/physician_gls/pdf/cml.pdf). RT-qPCR, quantitative real time-PCR; BM, bone marrow; PB, peripheral blood; MMR, mismatch repair..
Relative frequencies of recently identified molecular abnormalities in chronic myelomonocytic leukemia.
|Major class of genetic mutation||Classify||Gene||Frequency of mutation (%)|
|Epigenetic control||Histone modification||40|
|Transcription and nucleosome assembly||15|