Page 35 - 2019_10 resto del Mondo_web

The hematologic tumor microenvironment
defining feature, as revealed by Laurenti and colleagues. In fact, LT-HSC take longer than short-term HSC to enter the cell cycle. Cyclin dependent kinase-6 (CDK6) expression controls the exit from quiescence in human HSC.33 Consequently, enforced CDK6 expression can push LT- HSC to divide as quickly as short-term HSC. Human HSC heterogeneity and lineage commitment were dissected fur- ther in a subsequent study. The first lineage restriction appears to affect the CD19–CD34+CD38–CD45RA– CD49f+CD90+ HSC compartment’s generation of myelo- lymphoid committed cells which are devoid of erythroid differentiation capacity. The expression of the C-type lectin domain family 9 member A (CLEC9A) and CD34 in these cells can be used to distinguish CLEC9AhiCD34lo LT-HSC (with slow exit from quiescence) from CLEC9Alo CD34hi myelo-lymphoid-restricted HSC (with quicker entry into the cell cycle).34 These results help identify human HSC subsets and will be very useful to study their interactions with bone marrow microenvironments.
Interaction of tumor cells with their microenvironment
Mapping the bone marrow microenvironment in sickness and in health
The development of single-cell technologies has made it possible to generate an atlas of different tissues at single-cell resolution. A recent study by Dr. Aifantis’ group presented the transcriptional signatures of murine bone marrow vas- cular endothelial cells, perivascular cells and osteolineage/stromal cell populations under steady state or under stress (5-fluorocuracil), with a major emphasis on candidate cellular sources of key factors regulating hematopoiesis.35 For example, the loss of the delta-like canonical Notch ligand 4 (DLL4) in endothelial cells caused profound transcriptional changes, which drove myeloid skewing of HSC/progenitors.
Targeting the microenvironment in smoldering myeloma
Like other hematologic malignancies, multiple myeloma involves a multistep transformation process36 with con- comitant remodeling of the BM microenvironment,37 as shown by Ghobrial et al. However, studies on the human bone marrow microenvironment are frequently challenged by the scarcity and insufficient preservation of tissue biop- sies for detailed studies. A potential way to replace bone marrow biopsies might be to combine whole-exome sequencing of circulating tumor cells and cell-free DNA, which might help our understanding of disease heterogene- ity and evolution in multiple myeloma.38 Cell-free DNA reveals a similar clonal structure as bone marrow biopsies,39 potentially paving the path for less invasive mutational screening.
Investigating mechanisms regulating myeloma growth and dissemination using in vivo bone marrow imaging
Studies by Dr. Fooksman and others have showed the potential of intravital microscopy for studying the interac- tions of normal and mutant hematopoietic cells with their microenvironment. Antibody-secreting cells comprise mature plasma cells and more immature plasmablasts which can be identified by the expression of syndecan-1 (CD138), a marker with an unclear function until recently. CD138 has lately been found to promote the survival of
antibody-secreting cells through IL-6 and A proliferation- inducing ligand (APRIL).40 Therefore, ongoing studies are utilizing similar intravital imaging techniques to study the microenvironment in multiple myeloma and other hemato- logic malignancies.
The tumor microenvironment in chronic lymphocytic leukemia, plasma cell myeloma and myelodysplastic syndromes
Understanding and targeting tumor-microenvironment interactions in B-cell malignancies
Microenvironmental alterations can be putative thera- peutic targets in B-cell malignancies, as revealed by Ringshausen et al. The expression of protein kinase C beta II (PKCβ2) and downstream activation of NF-kappa B (NFkB) in BMSC is required for the survival of malignant B cells.41 Chronic lymphocytic leukemia (CLL) cells induce Notch2 signaling and complement C1q production by BMSC, which in turn inhibits glycogen synthase kinase 3 beta (GSK3β)-dependent degradation of β-catenin in CLL. Additionally, Notch2 activation in BMSC further stabilizes β-catenin in CLL through regulation of N-cadherin expres- sion. Consequently, inhibition of Notch or Wnt pathways has therapeutic effects in experimental CLL models.42
The biological and clinical roles of the microenvironment in chronic lymphocytic leukemia
Work in Dr. Hallek’s laboratory and others has illustrated how CLL becomes addicted to the microenvironment, and particularly to macrophages or nurse-like cells. A prominent example is the non-receptor tyrosine-protein kinase Lyn belonging to the SRC family, which is crucial both for B-cell receptor signaling and for microenvironmental support of the malignant cells.43 Lyn-deficient mice present a reduced CLL burden. However, the loss of Lyn in B cells only reduces B-cell receptor signaling, but does not affect CLL progression. In fact, Lyn is required in microenvironmental cells (and particularly macrophages) for the expansion of CLL cells.
Pre-clinical modeling of myelodysplastic syndromes in murine xenograft models
The clinical heterogeneity and molecular complexity of myelodysplastic syndromes (MDS) make these diseases arduous to model and study. However, xenograft models have emerged as useful tools for studying MDS. Co-trans- plantation of CD34+ cells with patient-derived BMSC has been reported in one study to increase long-term engraft- ment of human MDS in immunodeficient mice.44 In that study, patient-derived hematopoietic cells prompted healthy BMSC to acquire MDS-BMSC-like features. Consequently, cytokines produced by MDS BMSC favored the propagation of MDS after orthotopic interfemoral transplantation into immunodeficient mice. However, this finding contrasts with that of another study which found similar engraftment of MDS regardless of the presence of human BMSC.45 It is possible that technical differences and/or distinct diseases/stages underlie these divergent results. Moreover, due to recent advances in bioengineering and carrier materials, traditional xenotransplants are being progressively replaced by bioengineered humanized microenvironments. As one example, implantable scaffold
haematologica | 2019; 104(10)
1931