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Leung et al. J Transl Genet Genom 2023;7:79-86 https://dx.doi.org/10.20517/jtgg.2023.09 Page 69

Figure 1. Cytogenetic landscape of acute myeloid leukaemia (AML) patients younger than 60 years old in Hong Kong. Adapted from
[7]
Leung et al.

to improve overall survival based on randomized control trials or meta-analyses, including FLT3 inhibitor
[9]
midostaurin and monoclonal antibody against CD33 , and were approved by the US FDA for such
[8]
indications. Old and frail patients who are ineligible for standard treatment are primarily treated by low-
intensity treatment of palliative intent, including hypomethylating agents or low-dose cytarabine. More
recently, the addition of BCL2 inhibitor venetoclax to these agents was shown to improve overall survival,
with 30% of these patients able to live beyond 30 .
[10]

AML GENOMICS - A HISTORICAL PERSPECTIVE
Modern genomics in leukaemia research owes much to the phenomenal observation of recurrent
chromosomal translocations in patients with AML , APL , and CML by Dr. Janet Rowley and others
[2]
[3]
[11]
about 50 years ago, leading to the identification of oncogenic fusion genes, i.e., RUNX1-RUNX1T1,
PML-RAR, and BCR-ABL1, respectively. These discoveries have been instrumental in our understanding of
the molecular mechanisms of leukaemogenesis and formed the foundation for the subsequent development
of targeted therapies, including all-trans retinoic acid and tyrosine kinase inhibitors for APL and CML, both
of which have transformed the outcome of these patients. Since then, more chromosomal translocations in
AML have been described, many of which were predictive of clinical outcomes upon conventional
treatment. In addition, specific mutations have been identified, including those of CEBP and NPM1, which
were associated with a favorable prognosis, and those of RUNX1 and FLT3-ITD, which were associated with
an unfavorable prognosis .
[12]

The advent of next-generation sequencing (NGS) has made it possible to rapidly discover genetic mutations
in the cancer genome. Since the first report of whole-genome sequencing in AML in 2008 , the list of novel
[13]
gene mutations has expanded at an unprecedented rate [Figure 2]. In particular, mutations of genes
encoding for isocitrate dehydrogenase 1 and 2 were identified by NGS in patients with cytogenetically
normal AML [14,15] , and specific inhibitors are now available in clinics for AML carrying these mutations,
attesting to the power of genomic information in the development of target-specific therapy [16,17] . The
technologies have been generalized to solid cancers, forming the basis of The Cancer Genome Atlas
(TCGA). TCGA comprises more than 20,000 primary and matched normal samples spanning more than 30
cancer types and has become an important reference for cancer genome research(https://www.cancer.gov/
about-nci/organization/ccg/research/structural-genomics/tcga).