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Editorials
cers. Notably, mining the Oncomine database additionally revealed significant overexpression of both TYRO3 and MER in various B- and T-cell leukemia/lymphoma datasets, but not in AML (data not shown). This might suggest a potentially different mechanism of oncogenic signaling in lymphoid neoplasms involving all three receptor family members, as opposed to the clear role of AXL in FLT3-ITD+ AML; this could be a focus point for further investigations.
The new study by Dumas et al. described a resistance mechanism against the FLT3 inhibitor quizartinib, where both the FLT3-ITD mutation and the GAS6-AXL axis trig- ger important kinase signaling cascades. Their results sug- gest that a combination of FLT3- and AXL-specific inhibitors, or the exploitation of dual FLT3-AXL inhibitors (e.g. cabozantinib), might be beneficial in FLT3-ITD+ AML patients at risk of relapse. Furthermore, selective STAT5 inhibitors have the potential to become an effective tool for targeted and combinatorial therapy in AML.
In summary, FLT3 inhibitors display efficacy in the treat- ment of FLT3-ITD-driven AML, but more efficient targeting of AML blasts remains an unresolved medical need to fight therapeutic resistance, and to improve the poor overall sur- vival and quality of life of patients.
Funding
HAN and RM are supported by the Austrian Science Fund (FWF) [SFB-F04707, SFB-F06105, and under the frame of ERA PerMed (I 4218-B) and ERA-NET (I 4157-B)]. RM, HAN and AO were also generously supported by a private donation from Liechtenstein.
References
1. Daver N, Schlenk RF, Russell NH, et al. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019;33(2):299-312.
2. Dumas PY, Naudin C, Maetin-Lannerée S, et al. Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5- and hypoxia- dependent up-regulation of AXL.
Haematologica. 2019;104(10):2017-2027.
3. KiraneA,LudwigKF,SorrelleN,etal.WarfarinBlocksGas6-Mediated
Axl Activation Required for Pancreatic Cancer Epithelial Plasticity and
Metastasis. Cancer Res. 2015;75(18):3699-3705.
4. Wu X, Liu X, Koul S, et al. AXL kinase as a novel target for cancer ther-
apy. Oncotarget. 2014;5(20):9546-9563.
5. Lee HJ, Jeng YM, Chen YL, et al. Gas6/Axl pathway promotes tumor
invasion through the transcriptional activation of Slug in hepatocellular
carcinoma. Carcinogenesis. 2014;35(4):769-775.
6. Holstein E, Binder M, Mikulits W, et al. Dynamics of Axl Receptor
Shedding in Hepatocellular Carcinoma and Its Implication for
Theranostics. Int J Mol Sci. 2018;19(12).
7. Linger RMA, Keating AK, Earp HS, et al. TAM Receptor Tyrosine
Kinases: Biologic Functions, Signaling, and Potential Therapeutic
Targeting in Human Cancer. Adv Cancer Res. 2008;100:35-83
8. Paolino M, Penninger JM. The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy. Cancers
(Basel). 2016;8(10).
9. Yoshioka T, Shien K, Takeda T, et al. Acquired resistance mechanisms
to afatinib in HER2-amplified gastric cancer cells. Cancer Sci. 2019 Jun
4. [Epub ahead of print]
10. Mizuki M, Schwable J, Steur C, et al. Suppression of myeloid transcrip-
tion factors and induction of STAT response genes by AML-specific
Flt3 mutations. Blood. 2003;101(8)3164-3173.
11. NelsonEA,WalkerSR,XiangM,etal.TheSTAT5InhibitorPimozide
Displays Efficacy in Models of Acute Myelogenous Leukemia Driven
by FLT3 Mutations. Genes Cancer. 2012;3(7-8):503-511.
12. WingelhoferB,MaurerB,HeyesEC,etal.Pharmacologicinhibitionof
STAT5 in acute myeloid leukemia. Leukemia. 2018;32(5):1135-1146. 13. YoshimotoG,MiyamotoT,Jabbarzadeh-TabriziS,etal.FLT3-ITDup- regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD–specific STAT5 activation. Blood.
2009;114(24):5034-5043.
14. MaurerB,NivarthiH,WingelhoferB,etal.HighactivationofSTAT5A
drives peripheral T-cell lymphoma and leukemia. Haematologica. 2019
May 23. [Epub ahead of print]
15. Pham HTT, Maurer B, Prchal-Murphy M, et al. STAT5BN642H is a
driver mutation for T cell neoplasia. J Clin Invest. 2018;128(1):387-401. 16. Bowman RL, Busque L, Levine RL, et al. Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies. Cell Stem Cell.
2018;22(2):157-170.
17. Fuster JJ and Walsh K. Somatic Mutations and Clonal Hematopoiesis.
Circ Res. 2018;122(3):523-532.
18. Nogami A, Oshikawa G, Okada K, et al. FLT3-ITD confers resistance
to the PI3K/Akt pathway inhibitors by protecting the mTOR/4EBP1/Mcl-1 pathway through STAT5 activation in acute myeloid leukemia. Oncotarget. 2016;6(11):9189-9205.
19. Rhodes DR, Yu J, Shanker K, et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia. 2004;6(1):1-6.
Pediatric aplastic anemia treatment patterns and responses; power in the numbers
Lucy C. Fox1,2 and David S. Ritchie2,3
1Diagnostic Haematology, Peter MacCallum Cancer Centre; 2University of Melbourne and 3Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia
E-mail: DAVID S. RITCHIE - david.ritchie@mh.org.au doi:10.3324/haematol.2019.225870
In this edition of Haematologica, Rogers et al., represent- ing 25 individual institutions, collectively report on their findings of the diagnostic approaches, applied therapies and responses in a cohort of 314 pediatric patients (aged 1-20 years) with a diagnosis of aplastic anemia (AA) collected through the North American Pediatric Aplastic Anemia Consortium (NAPAAC).1 This study highlights a number of important messages; specif- ically the power of collated registry data in a rare disease, the need to retest and continually refine diagnostic crite-
ria to be fit for real-world purposes, the patterns of response and relapse to immunosuppressive therapy (IST) in a pediatric setting including the substantial differ- ences in outcomes from IST in children compared with that in adults, and the importance of allogeneic stem cell transplant (HCT) in the therapy of refractory or relapsed disease.
Although AA can affect people at any stage of life, with a well reported bimodal peak of age incidence observed in older children/young adults and those over sixty years,
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