A review on characterization of BCR – ABL transcript variants for molecular monitoring of chronic myeloid leukemia phenotypes

Figures & data

Figure 1. The Philadelphia chromosome [18]. Philadelphia chromosome described by Nowell and Hungerford indicated by an arrow. BCR/ABL breakpoints: m-BCR happens after exon 1, µ-BCR after exon 19, and the M-BCR beyond exon 13 or exon 14; ABL break points happen after the 2nd exon of the gene. Fusion oncogenes/mRNA transcripts which result from the breakpoints.

Figure 2. Pictorial representation of translocation (9; 22) and the resultant BCR – ABL transcripts associated with CML, AML and ALL [19].

Figure 3. BCR – ABL fusion gene oncogenesis leading to activation of different cellular processes and CML pathogenesis [34].

Figure 4. Molecular events leading to the expression of CML disease phenotype [35].

Figure 5. BCR–ABL1 domains and the targeting regions of the binding domains [37]. Numbering indicates amino acid residue location of each domain in BCR–ABL1 (asterisk indicates approximate location).

Figure 6. Defining response to treatment and minimal residual disease for patients diagnosed with chronic phase CML, treated with Imatinib [35].

Table 1. Summary of study reports on BCR – ABL transcript types and their association with hematological phenotypes/biological features.

STUDIES	TRANSCRIPTS DETECTED	REPORTED ASSOCIATED PHENOTYPES/BIOLOGICAL FEATUES
[64]	b3a2, b2a2	↑platelet counts and ↓WBC counts observed in patients harboring b3a2 transcript & exhibiting MDR1 gene over–expression
[63]	b3a2, b2a2	Transcript identification not statistically related to gender, WBC & Hgb values BCR – ABL transcript b3a2 more expressed in older patients & associated with ↑ platelet counts
[51]	b3a2, b2a2, e19a2	BCR–ABL1 transcript b3a2 more prevalent than b2a2 and in women Greater tumor charge of b2a2evidenced by ↑mean leukocyte count No difference for average number of platelets or hemoglobin concentration among patients expressing different transcripts
[10]	b3a2, b2a2, e1a2	BCR–ABL1 transcript b3a2 more prevalent than b2a2; co–expression of b3a2 /e1a2 in 0.56% patients Multiplex RT–PCR saves time in the detection of BCR–ABL1 transcript Occurrence of transcripts can assist in prognosis & treatment
[6]	b2a2, b3a2	BCR – ABL transcript b3a2 more frequent than b2a2 No significant association b/n transcripts & hematological/biological parameters Transcript types cannot be explained by clinical factors or CML phenotypes
[62]	b2a2, b3a2	BCR–ABL1 transcript b3a2 more frequent than b2a2 Co–expression of b3a2/b2a2 in 2 patients

Table 2. Summary of study reports on BCR – ABL transcript variants and their impact on achieving different types of response in patients taking various tyrosine kinase inhibitors.

STUDIES	TRANSCRIPTS DETECTED	REPORTED IMPACT ON MOLECULAR RESPONSES
[71]	b3a2, b2a2, b3a2/b2a2	BCR–ABL1 transcript b3a2 associated with warning molecular response to imatinib therapy (P = 0.047)
[70]	b3a2, b2a2, b3a2/b2a2	Patients expressing b2a2 transcript & treated with imatinib 400 mg daily exhibited ↓ CCyR (77%) compared with other TKIs (90–95%) Patients expressing b3a2, b3a2/b2a2 transcripts & treated with imatinib 400 mg daily exhibited similar CCyR to other TKI regimens (93–96%) Patients expressing b2a2 transcript and treated with imatinib 400 mg daily exhibited lower MMR and MR^4.5 rates compared with other TKI regimens Similar MMR and MR^4.5 rates observed in all TKIs for b3a2 transcripts Nilotinib therapy was associated with inferior MR^4.5 rates in both e13a2 and e14a2 transcript carriers compared with imatinib 800 or dasatinib therapy
[66]	e19a2, e1a2, e13a3, e14a3	e19a2, e1a2 associated with reduced probabilities of 1 year - CCyR & MMR e13a3, e14a3 associated with increased probabilities of 1 year - CCyR & MMR e19a2 associated with low probabilities of 2 year - EFS & PFS e1a2 associated with low probabilities of 2 year - EFS
[69]	b3a2, b2a2	Similar CCyR and MMR achievements for different transcripts (P = 0.921 and P = 0.489) Lower DMR & sDMR achievements for b2a2 (P = 0.008, P = 0.003) Slower sDMR achievement with IM therapy compared with 2GTKIs b2a2 transcript impedes the achievement of DMRs
[51]	b3a2, b2a2, e19a2	BCR–ABL1 b3a2 transcript associated with better (MMR) at 18 m post imatinib therapy Patients with b3a2 transcript may be associated with a better response to imatinib therapy

Radich JP. Another Philadelphia story. Haematologica. 2022;107(3):566.

 PubMed Web of Science ®Google Scholar

Avelino KY, Silva RR, da Silva Junior AG, et al. Smart applications of bionanosensors for BCR/ABL fusion gene detection in leukemia. J King Saud Univ-Sci. 2017;29(4):413–423.

 Web of Science ®Google Scholar

Pophali PA, Patnaik MM. The role of new tyrosine kinase inhibitors in chronic myeloid leukemia. Cancer J (Sudbury, Mass.). 2016;22(1):40.

 PubMed Web of Science ®Google Scholar

Frazer R, Irvine AE, McMullin MF. Chronic myeloid leukaemia in the 21st century. Ulster Med J. 2007;76(1):8.

 PubMedGoogle Scholar

Dixon AS, Constance JE, Tanaka T, et al. Changing the subcellular location of the oncoprotein BCR-ABL using rationally designed capture motifs. Pharm Res. 2012;29(4):1098–1109.

 PubMed Web of Science ®Google Scholar

Balatzenko G, Vundinti BR, Margarita G. Correlation between the type of BCR-ABL transcripts and blood cell counts in chronic myeloid leukemia – a possible influence of MDR1 gene expression. Hematol Rep. 2011;3(1):e3.

 PubMedGoogle Scholar

Bennour A, Ouahchi I, Achour B, et al. Analysis of the clinico-hematological relevance of the breakpoint location within M-BCR in chronic myeloid leukemia. Med Oncol. 2013;30:1–6.

 Web of Science ®Google Scholar

Nachi M, Kihel I, Entasoltane B, et al. Impact of the major BCR–ABL1 transcript type on clinical and biological parameters and molecular response in patients with chronic myeloid leukemia. Hematology/Oncology and Stem Cell Therapy. 2022.15:Iss.2, Article 9.

 PubMedGoogle Scholar

Chootawiriyasakul K, Chansung K. Multiplex PCR for identifying BCR-ABL fusion transcript types in Northeastern Thailand chronic myeloid leukemia patients. Srinagarind Med J. 2020;35(6):720–725.

 Google Scholar

Javed A, Mukhtar H, Kubra K, et al. Detection of BCR–ABL fusion gene and its transcript variants in chronic myeloid leukaemia patients–a multi – comparison study. JPMA. 2020;70(1748):10–5455.

 Google Scholar

Amin H, Ahmed S. Characteristics of BCR–ABL gene variants in patients of chronic myeloid leukemia. Open Med. 2021;16(1):904–912.

 Web of Science ®Google Scholar

Farhat-Maghribi S, Habbal W, Monem F. Frequency of BCR-ABL transcript types in Syrian CML patients. J Oncol. 2016;2016:8420853.

 PubMed Web of Science ®Google Scholar

Jain P, Kantarjian H, Patel KP, et al. Impact of BCR-ABL transcript type on outcome in patients with chronic-phase CML treated with tyrosine kinase inhibitors. Blood, J Am Soc Hematol. 2016;127(10):1269–1275.

 Google Scholar

Qin YZ, Jiang Q, Jiang H, et al. Prevalence and outcomes of uncommon BCR-ABL 1 fusion transcripts in patients with chronic myeloid leukaemia: data from a single centre. Br J Haematol. 2018;182(5):693–700.

 PubMed Web of Science ®Google Scholar

D’Adda M, Farina M, Schieppati F, et al. The e13a2 BCR-ABL transcript negatively affects sustained deep molecular response and the achievement of treatment-free remission in patients with chronic myeloid leukemia who receive tyrosine kinase inhibitors. Cancer. 2019;125(10):1674–1682.

 PubMed Web of Science ®Google Scholar