Page 17 - 2019_12-Haematologica-web

Editorials
combination with standard chemotherapy leading to bet- ter prognosis for these AML patients.
While the study by Wu et al.3 focuses only on FLT3- ITD+ AML, similar defects in the DDR are known to be associated with several other AML driver mutations, specifically the epigenetic regulators. Genes such as DNMT3A and TET2, which are very frequently mutated not only in the leukemic cells but also in the pre- leukemic clones, are known to regulate the DDR.11,12 Cells carrying mutations in these genes are known to have an increased propensity to accumulate DNA dam- age. Interestingly, they are also found in non-random association with FLT3-ITD and their concurrent occur- rence is sufficient for AML initiation. Similar to FLT3- ITD these pre-leukemic mutant clones tend to be chemo- resistant and they expand following elimination of leukemic cells by chemotherapy. The pre-leukemic clones are believed to evolve into leukemic cells due to inherent genomic instability and acquisition of addition- al mutations. The clinical relevance of alterations in the DDR in AML due to genetic mutations is underscored by the increase in survival with induction therapy dose escalation observed in patients carrying mutant DNMT3A but not in their wildtype counterparts.13 With better understanding of the driver mutations in AML and their role in normal cell functions, it is becoming appar-
Figure 1. FLT3-ITD and DOCK2 maintain the bal- ance between the DNA damage response and chemosensitivity. The positive signaling feedback between FLT3-ITD and DOCK2 upregulates the DNA damage response (DDR) through RAC1 leading to a decrease in chemosensitivity (CS) of acute myeloid leukemia (AML) cells. The balance can be tilted in favor of chemotherapy by downregulation of DOCK2 or inhibition of FLT3-ITD or DDR proteins which sen- sitizes the AML cells.
ent that an altered DDR is a common underlying theme in AML and pre-leukemic mutant cells. The research by Wu et al.3 emphasizes that combinatorial treatment strategies tailored to the specific driver mutation-depen- dent vulnerability in the DDR need to be explored fur- ther. A similar approach of inducing synthetic lethality by using PARP inhibitors in combination with standard chemotherapy in BRCA mutated gynecological cancers has led to improved patients’ outcomes in the clinic.14 Interestingly, FLT3-ITD+ leukemic cells can be sensitized to PARP inhibitors when used in combination with AC220, a second-generation FLT3 inhibitor, leading to enhanced survival.15 It is to be hoped that these studies will spur development of rational combinations of inhibitors of FLT3 signaling with DDR inhibitors leading to a broader range of options to improve patients’ out- comes and survival.
Acknowledgments
RP is supported by an award from the Ralph W. and Grace M. Showalter Research Trust and Indiana University School of Medicine. RK is supported by research grants from NIH- R01CA173852, R01CA134777, R01HL146137, and R01HL140961 and the Riley Children’s Foundation. The con- tent of this editorial is solely the responsibility of the authors and does not represent the views of the funding agencies.
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