Genomic and proteomic characterization of Philadelphia‐like B‐lineage acute lymphoblastic leukemia: A report of Indian patients

Abstract

Background The gold standard for the identification of Philadelphia (Ph)‐like acute lymphoblastic leukemia (ALL) patients is gene expression profiling. Because of its diverse nature, its identification is extremely difficult and expensive. On the genomic and proteomic landscape of Ph‐like ALL patients, there is a paucity of published literature from developing countries. Methods The authors used digital barcoded nCounter NanoString gene expression profiling for its detection, followed by molecular and proteomic characterization using fluorescence in situ hybridization and liquid chromatography–tandem mass spectrometry (LC–MS/MS). Results The authors found 32.05% Ph‐like ALL patients and their median age at presentation was considerably higher than Ph‐negative ALL cases (p = .0306). Furthermore, we identified 20% CRLF2 overexpressed cases having 8.33% CRLF2‐IGH translocation with concomitant R683S mutation and 8.33% CRLF2‐P2RY8 translocation. In 80% of CRLF2 downregulated cases, we identified 10% as having JAK2 rearrangement. Minimal residual disease‐positivity was more common in Ph‐like ALL cases (55.55% vs. 25% in Ph‐negative ALL cases). Immunoglobulin J chain (Jchain), small nuclear ribonucleoprotein SmD1 (SNRPD1), immunoglobulin κ constant (IGKC), NADH dehydrogenase (ubiquinone) 1 α subcomplex subunit 2 (NDUFA2), histone H2AX (H2AFX), charged multivesicular body protein 4b (CHMP4B), and carbonyl reductase (NADPH) (CBR1) proteins were identified to be substantially expressed in Ph‐like ALL patients, using LC–MS/MS. Gene enrichment analysis indicated that involvement of spliceosomal mediated messenger RNA splicing pathway and four microRNAs was statistically significant in Ph‐like ALL patients. Conclusions For the first time, we have described incidence, molecular, and proteomic characterization of Ph‐like ALL, in developing nations. Plain language summary In developing countries, detecting Philadelphia (Ph)‐like B‐lineage acute lymphoblastic leukemia is complicated and challenging due to its diverse genetic landscape. There is no well‐defined and cost‐effective methodology for its detection. The incidence of this high‐risk subtype is very high in adult cases, and there is an urgent need for its accurate detection. We have developed an online PHi‐RACE classifier for its rapid detection, followed by delineating the genomic and proteomic landscape of Ph‐like acute lymphoblastic leukemias for the first time in Indian patients.

Hematological, clinical, immunophenotypic characterization, and treatment outcomes of prognostically significant genetic subtypes of B‐lineage acute lymphoblastic leukemia: A report of 1021 patients from India

“…In the present study, we observed a higher frequency of 18% BCR::ABL1 fusion, followed by 4.9% ETV6::RUNX1 fusion, 3.8% TCF3::PBX1 fusion, 1.2% KMT2A::AFF1 fusion, and 26.67% BCR::ABL1 ‐like ALLs of all B‐ALL patients. The authors from high‐income and low‐income countries reported the recurrent genetic abnormalities (RGA) frequencies including 0.6%–35% BCR::ABL1 ‐positive ALLs, 0.8%–30.6% ETV6::RUNX1 , 0.8%–6.2% TCF3::PBX1 , 0.5%–19% KMT2A‐AFF1 , and 10%–33.1% BCR::ABL1 ‐like ALL cases 6,7,12‐15,17,18,20,28,31,32,34,37,41,49‐61 . The overall frequencies of RGAs and BCR::ABL1 ‐like ALL cases reported in the literature from low‐income and high‐income countries among B‐ALL patients (from India as well as other countries) are summarized in Table 3.…”

“…ABL1-positive ALLs, 0.8%-30.6% ETV6::RUNX1, 0.8%-6.2% TCF3:: PBX1, 0.5%-19% KMT2A-AFF1, and 10%-33.1% BCR::ABL1-like ALL cases. 6,7,[12][13][14][15]17,18,20,28,31,32,34,37,41,[49][50][51][52][53][54][55][56][57][58][59][60][61] monoclonal antibody clone type, and differences in flow cytometry methodology, processing, and data analysis. 74,76 Table 4 compares the reported frequencies of myeloid marker expression in B-ALL patients.…”

Pattern Recognition of Acute Lymphoblastic Leukemia (ALL) Using Computational Deep Learning

“…In fact, in lymphoblastic leukemia's, when the cells involved are B and T lymphocytes, when they are transformed, called lymphoblast's, and myeloid progenitor cells, such as granulocytes and monocytes, are involved. Gupta, D. G.,et al [34] has discussed another important classification concerns acute leukemia, which occurs more often in children and adolescents and is usually more aggressive and fast-moving and chronic forms, which mainly affect people in their 40s and 50s. Sekar, G.,et al [35] has discussed an environmental factors, including exposure to ionizing radiation following or connected to diagnostic or therapeutic procedures, for example, associated with environmental pollution, for example, the famous case of the explosion at the Chernobyl nuclear power plant or chemical carcinogens, including benzene, benzopyrene, toxic aldehydes and some heavy metals.…”

“…Chemotherapy is the primary treatment. However, depending on your subtype, you may receive alternative treatment Guo, M.,et al [33] In lymphoblastic leukemia's, when the cells involved are B and T lymphocytes, when they are transformed, called lymphoblast's, and myeloid progenitor cells Gupta, D. G.,et al [34] This disease occurs more often in children and adolescents and is usually more aggressive and fast-moving and chronic forms, which mainly affect people in their 40s and 50s…”

A surrogate molecular approach for the detection of Philadelphia chromosome–like B‐acute lymphoblastic leukemia

“…BCR::ABL1 ‐like/Ph‐like ALL has been incorporated as a provisional entity in the World Health Organization classification 2016, and it is considered an entity in the revised World Health Organization 2022 classification of the hematolymphoid neoplasms 10,11 . Ph‐like ALL cases share the same gene expression profile (GEP) as Ph‐positive ALL without expressing BCR::ABL1 fusion transcripts originating from Ph chromosome 1,6,8,12–43 . The peak incidence of Ph‐like ALL cases is in adolescents and young adults up to 33.1%, whereas it decreases with advancing age.…”