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Page 68 Leung et al. J Transl Genet Genom 2023;7:79-86 https://dx.doi.org/10.20517/jtgg.2023.09

[1]
heterogeneity that tends to evolve during the course of cancer treatment . This information has also
formed the theoretical basis of personalized cancer treatment based on the unique mutation compositions
of cancers at diagnosis and relapse.

Leukaemia has long been the foundational paradigm for new concepts in cancer biology and innovation in
therapeutic targeting. Phenomenal observations of chromosomal translocations in chronic myeloid
[2]
[3]
leukaemia (CML) and acute promyelocytic leukaemia (APL) , and the subsequent identification of
pathogenic fusion genes in these diseases, have led to the development of tyrosine kinase inhibitors and
differentiation agents. Both of these therapies have transformed the outcomes of patients, who can now be
cured based on chemotherapy-free regimens.

Acute myeloid leukaemia (AML) is a devastating disease worldwide, for which treatment outcomes are
unsatisfactory overall. The considerable inter- and intra-tumoral heterogeneities in AML have hampered
the development of effective treatments applicable to the multitude of AML subtypes. However, advances in
cancer genetics and genomics in recent years have empowered clinicians and scientists with the ability to
analyze leukaemia heterogeneities and clonal evolution at different treatment stages. This information has
[4]
begun to influence the clinical management of AML, improving outcomes for some of these patients .

We review the history of genomic research in AML in the past and how this knowledge has led to
improvements in the treatment outcomes of patients. We also discuss the future development of a
personalized approach to AML management.

ACUTE MYELOID LEUKAEMIA IN THE CLINICS – CURRENT STATE OF AFFAIRS
AML is a group of heterogeneous diseases with diverse morphologies, immunophenotypes, cytogenetics,
and genetics, sharing in common an abnormal increase in blasts in blood and bone marrow (BM). It occurs
in 3-5 patients per 100,000 individuals every year, and its incidence has increased in the past few decades. It
is a highly lethal disease and is the fifth deadliest cancer of all kinds, particularly in elderly patients who are
unfit to receive standard treatment. About 50% of AML cases carry normal cytogenetics, and they show on
average 2-4 recurrent mutations in different combinations, some of which are considered drivers and others
[5]
passengers in leukemogenesis . Some of these mutations are of prognostic significance. In particular,
NPM1 mutation and bZIP in-frame mutation of CEBPa are associated with a favorable response to
conventional chemotherapy, whereas FLT3-ITD is associated with a less favorable response. About
10%-15% of AML cases carry translocation t(8;21) (RUNX1::RUNX1T1) or inversion of chromosome 16
(CBFβ::MYH11), both of which involve components of the core-binding factor (CBF), which is a
heterodimeric transcription factor comprising the non-DNA-binding CBFβ chain and the DNA-binding
CBFα chain RUNX1. Half of these patients carry KIT mutations, which confer an inferior prognosis in this
AML subtype, which hitherto had a favorable response to conventional chemotherapy . Another 10% of
[6]
AML cases carry complex (≥ 3 karyotypic abnormalities) or monosomy karyotype (≥ 2 monosomies or 1
monosomy and one structural abnormality), and this subtype portends an extremely poor prognosis,
particularly those carrying TP53 mutations, which happen in half of the patients with this subtype . The
[7]
rest of AML cases are made up of diverse diseases with different karyotypic and genetic abnormalities
[Figure 1].

Despite the heterogeneity, AML has been managed by a one-size-fits-all approach in the past 4 decades. In
young and fit patients, intensive chemotherapy and allogeneic hematopoietic stem cell transplantation
(HSCT) are the mainstays of treatment. However, this approach has reached an impasse, and only 40% of
patients can survive long-term. A number of agents, when added to the chemotherapy regimen, were shown