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Page 4 of 10 Almeida et al. J Cancer Metastasis Treat 2021;7:57 https://dx.doi.org/10.20517/2394-4722.2021.108

out the absence of EGFR expression in some AML cell lineages and primary cells [2,6,8,35] . However,
[12]
Mahmud et al. demonstrated that 11% (57/511) and 18% (93/511) of AML patients express high levels of
+
total and phosphorylated EGFR, respectively, when compared to CD34 healthy bone marrow samples,
suggesting that this subset could benefit from EGFR TKI therapy. Accordingly, only leukemic cell lines
positive for EGFR were responsive to cetuximab-induced cell death . Specifically, in APL samples, our
[5]
group detected total and phosphorylated EGFR protein in 6/21 (28.5%) and 4/21 (19%) of APL patients,
respectively, but not in CD34 healthy bone marrow samples. In addition, we demonstrated that gefitinib
+
enhanced the all-trans retinoic acid (ATRA)-induced differentiation in EGFR-negative APL cells lines NB4
and NB4-R2 (de Almeida LY and Rego EM, own unpublished observation, 15 June 2021).

The reason EGFR expression affects the prognosis of patients with AML has not been addressed so far.
Interestingly, increased HSC mobilization induced by granulocyte colony-stimulating factor (G-CSF) was
achieved in healthy donors after the pharmacological inhibition of EGFR activity through activation of
GTPase Cdc42 (cell division control protein-42) . In addition, in a chemotherapy-induced
[36]
myelosuppression model, the combination of G-CSF and EGF was synergistic for regeneration of the bone
marrow compared to either G-CSF or EGF alone, and EGF increased G-CSF receptor expression following
exposure to 5-fluorouracil. Conversely, G-CSF treatment increased both EGFR and phosphorylation of
EGFR in hematopoietic stem/progenitor cells. Considering that in AML sensitization of leukemic cells with
hematopoietic growth factors may enhance the cytotoxicity of chemotherapy, the association of G-CSF and
EGFR TKI may be beneficial . Accordingly, a Japanese nationwide retrospective analysis of the outcome of
[37]
cord blood transplantation for AML showed that the addition of G-CSF-combined cytarabine to a total
body irradiation plus cyclophosphamide conditioning regimen resulted in a significantly better disease-free
[38]
survival and OS and a reduced relapse rate . It is conceivable that the association of EGFR TKI to G-CSF
could increase the sensitization of leukemic cells to cytotoxic therapy and further improve the outcome of
HCT in AML.

EGFR LIGANDS EXPRESSION IN AML
The mRNA expression of AREG , HB-EGF , and EREG genes, whose translational products are EGFR
[40]
[39]
[41]
ligands, were previously detected in AML samples, but their prognostic relevance has not been defined. The
AREG expression pattern has been recognized to be useful to distinguish AML from B-cell lymphoblastic
leukemia . Similarly, HB-EGF is expressed in human myeloid and T, but not B, lymphoid cell lines .
[39]
[40]
Moreover, the main differentially expressed gene between arginase-resistant and -sensitive AML is EREG,
[41]
which encodes the protein EPR . Indeed, EREG overexpression in solid tumors was associated with cancer
cell proliferation via EGFR/MAPK/PI3K/AKT signaling . However, more investigation is necessary to
[42]
understand the biological implications of EREG signaling in AML.
Wu et al. evaluated the urine of 18 patients with APL and found that they had significantly elevated levels
[43]
of EGF when compared to healthy patients. Besides, lower and higher levels of EGF excretion were
associated with complete remission and clinical recurrence, respectively, in patients with APL. Thus, these
authors suggested that quantifying EGF levels may serve as a means of monitoring this disease. However,
the significant correlation between EGF and creatinine detected in the urine did not have a direct
[44]
relationship with EGF levels in blood serum or plasma . It suggests that EGF is mainly derived from
kidney biosynthesis secretion and that the levels of EGF in the urine are probably a reflection of treatment
with ATRA rather than that released by the APL cells themselves. In the bone marrow microenvironment,
+
CD8 T cells promoted LSPCs expansion via upregulation of IL-3 through EGF/EGFR signaling in
favorable-risk, but not intermediate- or adverse-risk, AML . In vitro, the pro-proliferative effect of CD8 T
[11]
+
[11]
cells on LSPCs was abrogated in the presence of anti-EGFR antibodies . The differential response of LSPC