January-February 2020, Volume 17, Issue 1
Mapping Functional Susceptibilities in AML
Published on: January 06, 2020
Acute myeloid leukemia (AML) is characterised by recurrent genetic driver mutations that cluster in a non-random manner and define prognosis. These patterns of mutation clusters have led to the hypothesis that discrete mutational clusters, for example, signalling molecular activation and dominant negative impairment of transcription factor function, can collaborate to induce AML. Epigenetic lesions are among the most frequent clusters associated with AML and lead to changes in DNA methylation or histone modifications, resulting in broad changes in gene expression.
For the 2019’s Year’s Best, we have chosen to recognise important functional genetic work that illuminates how mutations in AML contribute to leukemogenesis, providing rationale for precision-based therapies aimed at specific disease biology. Mutations in splicing factors such as SF3B1 or SRSF2 are thought to be rare in de novo AML but are more common in myelodysplastic syndrome (MDS) and AML arising from MDS. Each splicing gene has relatively specific effects on RNA splicing and recognise different intron-exon boundaries. Dr. Akihide Yoshimi and colleagues1 examined splicing in large cohorts of AML and unexpectedly found a significant percentage of patients who have aberrant splicing characteristic of SRSF2 mutations (SRSF2mut), even though many of these patients had not been initially noted to have SRSF2mut. Working backwards from the RNA sequencing data, they were able to identify SRSF2mut within a significant percentage of AML transcriptomes, that there was a significant correlation between SRSF2mut and IDH2mut, and that this combination conferred an adverse prognosis.
Subsequently, through use of human data and extensive and elegant mouse model systems, the researchers were able to show potent cooperativity between IDH2mut and SRSF2mut, leading to acceleration of myeloid disease. Mechanistically, IDH2mut led to 2-hydroxyglutarate accumulation and inhibition of a variety of epigenetic enzymes including TET2. DNA cytosine methylation, regulated in part by TET2, is an important promoter regulation but also controls splice site recognition and RNA-polymerase II (RNA-Pol II) mediated transcriptional elongation. Here, Dr. Yoshimi and colleagues were able to bring together the effect of seemingly distinct biologic pathways and demonstrate potent interaction at the level of DNA methylation, splice site choice, RNA-Pol II transcriptional elongation, and consequent functional effects on the integrator complex through aberrant splicing of INTS3. Finally, they were able to show that aberrant INTS3 splicing is seen in several subtypes of AML but is not seen in normal bone marrow or in other forms of cancer. Moreover, aberrant INTS3 splicing could be partially rescued by treatment with a DNA methyl transferase inhibitor.
These data are important because they demonstrate that cooperative mutational patterns are driven by underlying biologic synergies. Understanding these biologic mechanisms enables clinicians to functionally subclassify AML groups and moves beyond pattern recognition of AML mutations in disease prognostication. This functional understanding will help develop a map detailing mechanism-driven precision therapeutic approaches to improve survival (Figure). These biologic insights pave the way for novel therapeutic classes, such as modulators of aberrant splicing, to be used in specific subgroups of MDS or AML, perhaps in combination with DNA methyl transferase inhibitors.
An honourable mention goes to the work of Dr. Steffen Boettcher and colleagues, who in a similar careful manner functionally characterized a curated number of missense and truncated variants of TP53 in AML and MDS.2 Using elegant CRISPR-Cas9 gene editing techniques, researchers observed that these mutations have a dominant-negative effect with loss of DNA binding after DNA damaging agents, and importantly do not appear to lead to gain of function. Clinically, these mutations cause chemotherapy resistance and dismal long-term outcomes for patients. It follows that improving outcomes for these patients will require therapeutic approaches to counter the dominant negative effect of mutant TP53, to restore the normal DNA damage response.
Precision medicine approaches have revolutionized the treatment of monogenic diseases such as chronic myeloid leukemia; however, similar success in targeting oncogenic drivers has not been realised in AML where multiple pathways and multiple mutations to genes with variable functional outcome are involved. These refined mechanistic studies reveal cooperativity in oncogene mutation and functional impact, helping to deconvolute the steps to leukemic transformation while providing a map to rationally intervene therapeutically and subvert the function of leukemogenic mutations.
Another honourable mention for AML therapy is for a late breaking abstract presented at the 2019 ASH Annual Meeting. In the QUAZAR AML-001 study, Dr. Andrew Wei and colleagues have used an oral version of azacitidine (CC486) as maintenance therapy in patients who have achieved remission after induction and consolidation chemotherapy for AML.3 In a predominantly elderly population, CC-486 maintenance led to improved overall survival (24.7 vs. 14.8 months vs. placebo, p=0.0009), albeit without an apparent plateau in the survival curves. It appears likely that this study will define a new standard of care for elderly patients with AML. Taken together these papers significantly advance our understanding of functional genetics driving AML disease biology and add to a promising and evolving range of therapeutic options which will ultimately improve survival and outcomes for patients with MDS and AML.
Yoshimi A, Lin KT, Wiseman DH, et al. Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis. Nature. 2019;574:273-277.
Boettcher S, Miller PG, Sharma R, et al. A dominant-negative effect drives selectin of TP53 missense mutations in myeloid malignancies. Science. 2019;365:599-604.
Wei AH, Döhner H, Pocock C, et al. The QUAZAR AML-001 Maintenance Trial: Results of a phase III international, randomized, double-blind, placebo-controlled study of CC-486 (oral formulation of azacitidine) in patients with acute myeloid leukemia (AML) in first remission. ASH. 2019;LBA-3.
Conflict of Interests
Dr. Lane has previously participated in an advisory board and received research funding from Celgene. Dr. Henden indicated no relevant conflicts of interest.
back to top