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Editorials
translocation t(9;11)(p22;q23), typically associated with the M4 or M5 French-American-British subtypes of human AML. An MLL-AF9-induced AML mouse model is widely used to study AML. Hanoun et al. showed that MLL-AF9- induced AML cells disrupt bone marrow HSC niche function through alteration of the niche compartments and decrease of the expression of MSC-derived Cxcl12, Scf, Vcam1, and increased expression of Opn.15 These phenotypes in the MLL-AF9-induced AML bone marrow niche mirrored those in the Twist1-deficient bone marrow niche observed by Liu et al.2 They also found that a Twist1-deficient niche promot- ed progression of MLL-AF9-induced AML. By using RNA- sequencing, the authors found that Jagged-2 is significantly increased in the stromal cells from the Twist1-deficient bone marrow niche and that Notch receptors are upregulated on leukemia cells. Pharmaceutical inhibition of Notch signaling partially inhibited the leukemia progression. These data indicate that AML progression is a closed loop, AML cells impair the normal bone marrow niche and alter the niche to support AML cell survival and progression. Targeting the leukemia cell - bone marrow niche loop could be an efficient strategy for leukemia therapy. Jagged-2/Notch signaling is a potential target.
Relevance of understanding the hematopoietic niche in human disease
Bone marrow failure syndromes, including aplastic ane- mia and myelodysplastic syndromes result from cell- and non-cell-autonomous dysregulation. Similarly, there is increasing evidence of the role of the bone marrow niche in leukemogenesis. Non-cell-autonomous dysregulation is linked to changes in the signals from innate and adaptive immune environments, and endothelial and mesenchymal lineage cells. Big data analyses based on matrix analyses of combined large data sets from single-cell RNA sequencing, flow/mass cytometry, metabolomics and proteomics mass spectrometry, as well as sophisticated microanatomical analyses are generating multiple hypotheses on the specific dissection of the interacting signal networks that connect the HSC niche cells of the bone marrow. These hypotheses require exquisite analysis and validation in mutant animal
Assessment of iron deficiency
Chaim Hershko
models and in therapeutic approaches when pharmacologi- cal tools to specific targets allow analyses of efficacy and safety in patients with hematologic diseases.
References
1. GaoX,XuC,AsadaN,FrenettePS.Thehematopoieticstemcellniche: from embryo to adult. Development. 2018;145(2). pii: dev139691.
2. Liu X, Ma Y, Li R, et al. Niche TWIST1 is critical for maintaining normal hematopoiesis and impeding leukemia progression. Haematologica 2018;103(12):1969-1979.
3. Barnes RM, Firulli AB. A twist of insight - the role of Twist-family bHLH factors in development. Int J Dev Biol. 2009;53(7):909-924.
4. Dong CY, Liu XY, Wang N, et al. Twist-1, a novel regulator of hematopoietic stem cell self-renewal and myeloid lineage develop- ment. Stem Cells. 2014;32(12):3173-3182.
5. ArthurA,CakourosD,CooperL,etal.Twist-1enhancesbonemarrow mesenchymal stromal cell support of hematopoiesis by modulating CXCL12 expression. Stem Cells. 2016;34(2):504-509.
6. MiraouiH,SevereN,VaudinP,PagesJC,MariePJ.Molecularsilencing of Twist1 enhances osteogenic differentiation of murine mesenchymal stem cells: implication of FGFR2 signaling. J Cell Biochem. 2010;110(5):1147-1154.
7. Zhao Z, Rahman MA, Chen ZG, Shin DM. Multiple biological func- tions of Twist1 in various cancers. Oncotarget. 2017;8(12):20380- 20393.
8. Peled A, Petit I, Kollet O, et al. Dependence of human stem cell engraft- ment and repopulation of NOD/SCID mice on CXCR4. Science. 1999;283(5403):845-848.
9. GreenbaumA,HsuYM,DayRB,etal.CXCL12inearlymesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature. 2013;495(7440):227-230.
10. Mendez-FerrerS,FrenettePS.Hematopoieticstemcelltrafficking:reg- ulated adhesion and attraction to bone marrow microenvironment. Ann N Y Acad Sci. 2007;1116:392-413.
11. Sharabi AB, Aldrich M, Sosic D, et al. Twist-2 controls myeloid lineage development and function. PLoS Biol. 2008;6(12):e316.
12. WangN,GuoD,ZhaoYY,etal.TWIST-1promotescellgrowth,drug resistance and progenitor clonogenic capacities in myeloid leukemia and is a novel poor prognostic factor in acute myeloid leukemia. Oncotarget. 2015;6(25):20977-20992.
13. ChenCC,YouJY,GauJP,etal.Favorableclinicaloutcomeandunique characteristics in association with Twist1 overexpression in de novo acute myeloid leukemia. Blood Cancer J. 2015;5:e339.
14. Li X, Marcondes AM, Gooley TA, Deeg HJ. The helix-loop-helix tran- scription factor TWIST is dysregulated in myelodysplastic syndromes. Blood. 2010;116(13):2304-2314.
15. Hanoun M, Zhang D, Mizoguchi T, et al. Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell. 2014;15(3):365- 375.
Professor Emeritus, Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel
E-mail: hershkoc@netvision.net.il doi:10.3324/haematol.2018.205575
According to a study involving 187 countries,1 the global prevalence of anemia in 2010 was 33% and it was responsible for 68 million years lived with dis- ability . Iron deficiency was the top cause of anemia, with children below 5 years and women having the highest bur- den. In addition to iron deficiency, which was the most common etiology globally, other leading causes of anemia vary widely by geography, age, and sex.
Traditionally, the diagnosis of iron deficiency anemia (IDA) rests on simple measurements of serum iron, transfer- rin and ferritin in subjects with microcytic hypochromic anemia. However, iron deficiency and other conditions associated with anemia, such as the anemia of chronic dis- ease and hemoglobinopathies often coexist, requiring fur- ther refinement of diagnostic strategies. The study report- ed by Kanuri et al.2 in this issue represents an effort to opti-
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