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Figure 1. Schematic representation of the EGFR signaling axis and its most important downstream targets in the AML microenvironment.
+
EGFR ligands in the bone marrow microenvironment phosphorylate EGFR receptors on the surface of LSPC or CD8 T cells, leading to
the production and release of IL-3. In turn, IL-3 induces proliferation signals in LSPCs, promoting the expansion of AML cells. Direct
arrows represent direct interactions, and the dotted arrow represents indirect effects. AML: Acute myeloid leukemia; LSPCs: leukemia
stem/progenitor cells; IL-3: interleukin-3; EGFR: epidermal growth factor receptor; EGF: epidermal growth factor; TGF-α: transforming
growth factor-alpha; AREG: amphiregulin; HB-EGF: EGF-like heparin-binding factor; BTC: betacellulin; EPR: epiregulin; SFK: src family
kinases; PI3K: phosphatidylinositol 3-kinase; AKT: protein kinase B; JAK2: Janus-activated kinase 2; JAK: Janus-activated kinase; STAT5:
signal transducer and activator of transcription 5. Image created using BioRender.com.

The aberrant expression and/or mutation of EGFR, as well as the continuous stimulation of this receptor
due to the greater presence of its ligands in the tumor microenvironment, have a direct implication in the
pathogenesis and progression of cancer since they are associated with increased tumor growth, invasion,
and metastasis . For this reason, EGFR has been described as an important therapeutic target in several
[30]
malignant neoplasms, such as pancreas, colorectal, lung, breast, and head and neck carcinomas . However,
[31]
in hematological malignancies, EGFR mutations are very rare [3,4,32] , and its expression and clinical response
to EGFR TKI in AML is still controversial.

EGFR EXPRESSION IN AML
Aberrant expression of EGFR has been associated with aggressive behavior in a wide range of solid
tumors , but the role and pattern of EGFR expression in hematological malignancies are still not well
[31]
understood. Specifically, in AML, EGFR mRNA was detectable in approximately 35% of patients and
correlated with decreased overall (OS) or event-free survival [5,33] . Notably, although acute promyelocytic
leukemia (APL) is the most curable form of AML in adults, the EGFR gene expression in 5/29 (17.5%) of the
patients was also associated with an adverse clinical outcome . At the protein level, some studies pointed
[34]