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Editorials
References
1. Byrd JC, Mrozek K, Dodge RK, et al. Cancer, Leukemia Group B. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood. 2002;100(13):4325- 4336.
2. Sallmyr A, Fan J, Datta K, et al. Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: implications for poor prognosis in AML. Blood. 2008;111(6):3173-3182.
3. WuM,LiL,HamakerM,SmallD,DuffieldAS.FLT3-ITDcooperates with Rac1 to modulate the sensitivity of leukemic cells to chemother- apeutic agents via regulation of DNA repair pathways. Haematologica. 2019;104(12):2418-2428.
4. Seedhouse CH, Hunter HM, Lloyd-Lewis B, et al. DNA repair con- tributes to the drug-resistant phenotype of primary acute myeloid leukaemia cells with FLT3 internal tandem duplications and is reversed by the FLT3 inhibitor PKC412. Leukemia. 2006;20(12): 2130-2136.
5. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464.
6. Marei H, Malliri A. Rac1 in human diseases: the therapeutic poten- tial of targeting Rac1 signaling regulatory mechanisms. Small GTPases. 2017;8(3):139-163.
7. Wu M, Hamaker M, Li L, Small D, Duffield AS. DOCK2 interacts with FLT3 and modulates the survival of FLT3-expressing leukemia cells. Leukemia. 2017;31(3):688-696.
8. Chatterjee A, Ghosh J, Ramdas B, et al. Regulation of Stat5 by FAK and PAK1 in oncogenic FLT3- and KIT-driven leukemogenesis. Cell Rep. 2014;9(4):1333-1348.
9. Nishikimi A, Uruno T, Duan X, et al. Blockade of inflammatory responses by a small-molecule inhibitor of the Rac activator DOCK2. Chem Biol. 2012;19(4):488-97.
10. Sakurai T, Uruno T, Sugiura Y, et al. Cholesterol sulfate is a DOCK2 inhibitor that mediates tissue-specific immune evasion in the eye. Sci Signal. 2018;11(541)pii:eaao4874.
11. Guryanova OA, Shank K, Spitzer B, et al. DNMT3A mutations pro- mote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nat Med. 2016;22(12):1488-1495.
12. PanF,WingoTS,ZhaoZ,etal.Tet2lossleadstohypermutagenicity in haematopoietic stem/progenitor cells. Nat Commun. 2017;8:15102.
13. Sehgal AR, Gimotty PA, Zhao J, et al. DNMT3A mutational status affects the results of dose-escalated induction therapy in acute myel- ogenous leukemia. Clin Cancer Res. 2015;21(7):1614-1620.
14. LordCJ,AshworthA.PARPinhibitors:syntheticlethalityintheclin- ic. Science. 2017;355(6330):1152-1158.
15. Maifrede S, Nieborowska-Skorska M, Sullivan-Reed K, et al. Tyrosine kinase inhibitor–induced defects in DNA repair sensitize FLT3(ITD)-positive leukemia cells to PARP1 inhibitors. Blood. 2018;132(1):67-77
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Fine tuning of p53 functions between normal and leukemic cells: a new strategy for the treatment of chronic lymphocytic leukemia
Tatjana Stankovic
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK E-mail: TATJANA STANKOVIC - t.stankovic@bham.ac.uk doi:10.3324/haematol.2019.230896
Pathophysiology and current therapies in chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is the most fre- quent leukemia in western countries. It is characterized by the accumulation of mature B lymphocytes in the peripheral blood, peripheral lymphoid organs and bone marrow. CLL displays a heterogeneous clinical course, ranging from protracted indolent disease with no require- ment for treatment in some patients to rapid disease pro- gression and subsequent treatment refractoriness in oth- ers.1-3
CLL progression is a reflection of the complex interplay between genomic drivers of disease and interactions with the microenvironment.4 Whole genome/exome profiling by next-generation sequencing has revealed that the clon- al composition of CLL is constantly reshaped during dis- ease progression. It has been proposed that CLL exhibits a stochastic model of progression with the existence of a ‘trunk’ tumor population and numerous ‘branches’ that can act as tumor progenitors. According to this model, the subclonal topography of CLL arises over time as a result of an initial driver mutation which leads to malig- nant transformation and is observed in all tumor cells – the trunk population. This is followed by secondary driv- er mutations in distinct subclones which are selected by intraclonal competition or treatment, and are likely to contribute to disease progression. Finally, CLL relapse has
been attributed to the expansion of highly fit, often treat- ment-selected subclones (branches) carrying mutations in the DNA damage response (DDR) genes TP53 and ATM, SF3B1 or NRAS.5,6 As a result, a significant proportion of relapsed/refractory CLL can be attributed to the function- al loss of the DDR.
For several decades, alkylating agents and purine analogs were the principal therapies for CLL, augmented by the addition of monoclonal antibodies. The last decade has seen an expansion in the number of com- pounds targeting specific aspects of the CLL phenotype, from the interactions of tumor cells with the microenvi- ronment and B-cell receptor signaling to anti-apoptotic cellular pathways, heralding a new era of CLL therapy based on targeted treatment approaches.7-10 In particular, new inhibitors of signaling pathways that are critical to CLL survival and proliferation, such as Bruton tyrosine kinase (BTK), phosphoinositide-3 kinase (PI3K), and the anti-apoptotic protein Bcl-2, have changed the manage- ment of many CLL patients.
Despite the array of available therapeutic options, CLL remains, at present, an incurable condition.11 Firstly, the acquisition of DDR gene defects such as TP53 deletions and/or mutations renders CLL patients refractory to con- ventional chemoimmunotherapies. The clinical response to the BTK inhibitor, ibrutinib, is encouraging for some but not all refractory tumors.12 Secondly, clonal selection
haematologica | 2019; 104(12)