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Page 6 of 14 Tosato et al. J Cancer Metastasis Treat 2021;7:52 https://dx.doi.org/10.20517/2394-4722.2021.120

mouse models may be relevant to human MDS with del(5q) in that the APC gene, located on 5q23, is
[46]
deleted in more than 95% of cases of (5q) MDS .
A series of other experiments provided evidence of premalignant hematopoietic disorders initiated by non-
hematopoietic cells. In one example, newborn mice lacking NF-κB inhibitor-α (IκBα/Nfkbia) developed
myeloproliferative disease affecting the granulocyte, erythroid monocyte/macrophage lineages. This
outcome could not be reproduced by the selective conditional deletion of IκBα in myeloid lineage cells. By
contrast, coculture of IκBα deficient hepatocytes with wild type bone marrow cells induced an increase of
[47]
multilineage (granulocyte/erythroid/monocyte/macrophage) colonies . In another example, the
conditional deletion of the retinoblastoma protein (Rb1B) in the hematopoietic system produced a
myeloproliferative syndrome with loss of HSC. This phenotype was not attributable to Rb1B deficiency in
the HSC, as it could not be reproduced by deleting Rb1B from the bone marrow HSC, but instead to Rb1B
deficiency in the bone marrow microenvironment as demonstrated in transplant experiments . Also,
[48]
inactivation of Mind bomb-1 (Mib1), a protein that regulates Notch signaling by facilitating the
internalization of Notch ligands, induced a myeloproliferative disorder with progressive tissue accumulation
of immature granulocytes and death of the mice by approximately 20 weeks. Transplantation of normal
bone marrow into the Mib1-null mice reproduced the myeloproliferative syndrome in the transplanted
[49]
graft, implicating the recipient bone marrow microenvironment . Furthermore, mice with Crebbp (CREB-
binding protein) haploinsufficiency, display increased myeloid cell differentiation, loss of HSC and
hematopoietic progenitors, and are prone to developing hematological malignancies with age. These
abnormalities correlated with increased expression of the endothelial adhesion molecule 1 and CDH5/VE-
cadherin in a subset of bone marrow endothelial cells from the Crebbp mice . In addition, mice deficient
+/-
[50]
of retinoic acid receptor gamma (Rarg) display progressive expansion of granulocyte/macrophage
progenitors and mature granulocytes in the bone marrow and blood. Since bone marrow from normal mice
developed a similar myeloproliferative disorder after transplantation into Rarg-deficient mice, intrinsic
deficiency of Rarg in the hematopoietic cells is unlikely the cause of the myeloproliferative syndrome .
[51]
Another example linked activating mutations of Ptpn11 in the mouse bone marrow mesenchymal stem
cells, but not within the osteoblasts or endothelial cells, to the development of and progression of
[52]
myeloproliferative disease . Ptpn11 codes for the Src homology region 2 domain-containing phosphatase 2
(SHP2). Mechanistically, the process was attributed to a pro-inflammatory bone marrow milieu sustained
by interleukin-1β . This mouse model could be relevant to a proportion of patients with juvenile
[52]
myelomonocytic leukemia arising either in patients with Noonan syndrome, an autosomal dominant
disorder characterized by skeletal and heart defects, or without Noonan syndrome. Noonan syndrome is
attributed to germline mutations of Ptpn11 that affect the SHP2 phosphatase domains . In addition, one
[53]
third of patients with juvenile myelomonocytic leukemia without the syndrome harbor somatic mutations
of Ptpn11, which were predicted to cause a gain of function in SHP2 that was proposed to act as an
[54]
oncoprotein in these myeloid leukemias .

MALIGNANT CELLS REMODEL THE BONE MARROW NICHE
Evidence that niche pathology drives bone marrow hematological malignancies comes primarily from
genetic experiments in mice outlined in the previous section, whereas clinical evidence for this process is
currently limited. Only rare cases of MDS and AML displayed genetic mutations in bone marrow
mesenchymal cells, which differed from those detected in the malignant cells, supporting an oncogenic role
of non-hematopoietic niche factors [55-58] . However, these mutations were of unknown oncogenic potential.
Additional support for a primary pro-oncogenic role of the bone marrow microenvironment comes from a
small series of leukemias arising in allogeneic transplant recipients, where some of the leukemias were of
normal donor derivation and may thus have arisen because of their localization in the recipient pathogenic