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Page 2 of 22 García-Pardo et al. J Cancer Metastasis Treat 2021;7:62 https://dx.doi.org/10.20517/2394-4722.2021.103

Keywords: Chronic lymphocytic leukemia, angiogenic factors, CLL microenvironment, CLL migration and survival,
antiangiogenic therapy

INTRODUCTION
Chronic lymphocytic leukemia (CLL), the most common leukemia in Western countries, is characterized by
+
the clonal proliferation and accumulation of CD5 B lymphocytes in the peripheral blood and lymphoid
organs . The degree of organ infiltration serves to classify CLL into different clinical stages, following the
[1-4]
[6]
criteria established by Rai (stages 0-IV) and Binet (stages A-C) . According to these criteria, the CLL stage
[5]
0/A represents low-risk, I-II/B is an intermediate-risk, and III-IV/C represents high-risk. CLL staging is also
useful to determine the need for treatment. Current therapies for CLL include the combination fludarabine-
cyclophosphamide-rituximab, as well as inhibitors of the B-cell receptor (BCR) signaling pathway, such as
ibrutinib/acalabrutinib (Bruton’s tyrosine kinase inhibitors) and idelalisib (phosphatidylinositol 3-kinase-δ
inhibitor) . An increasing number of CLL cases are now been treated with the Bcl-2 antagonist venetoclax,
[7,8]
either as monotherapy or combined with other therapeutic agents . Although many patients respond to
[7,8]
treatment and some achieve remission, CLL remains an incurable disease.
Clinically, CLL is very heterogenous, with good or poor prognosis mostly determined by the presence of
specific markers, particularly mutated (M-CLL) or unmutated (U-CLL) immunoglobulin heavy-chain
variable region (IGVH) . U-CLL originates from B cells that have not experienced the germinal center and
[1-4]
represents an aggressive disease, whereas M-CLL originates from germinal center-differentiated B cells and
usually represents a mild form of the malignancy . Other established prognostic markers for CLL are CD38
[9]
and CD49d (the α subunit of the α4β1 integrin), whose elevated expression on CLL cells (> 30%) is
associated with a poor outcome [10,11] . CLL tumors also accumulate multiple gene mutations and/or deletions,
such as those affecting the p53 protein, whose loss of function is related to resistance to chemotherapy .
[4]
Whole-genome sequencing analyses have identified genes that are recurrently mutated in CLL, including
notch1 (NOTCH1) and myeloid differentiation primary response gene 88 (MYD88) . NOTCH1 mutations
[12]
[12]
are mainly detected in U-CLL cases, while MYD88 mutations are predominant in M-CLL . NOTCH1
[13]
mutations are also linked to poor CLL prognosis and high CD49d expression . Recurrent mutations have
also been found in genes affecting crucial signaling pathways in CLL, such as those induced by the BCR,
[4]
NF-κB transcription factor, or MAPK-ERK system . Epigenomic changes are also frequent in CLL, with
different patterns in U-CLL and M-CLL cases .
[4]
CLL progression is determined by the infiltration of bone marrow and secondary lymphoid organs by the
malignant cells. This process is mostly mediated by the α4β1 integrin and the chemokine/receptor axes
CXCL12/CXCR4 and CCL21/CCR7 [14,15] . MMP-9, CD44, particularly the CD44v6 variant, and CD38 have
also be shown to play roles in CLL cell migration to tissues [15-17] . Localization in lymphoid niches is beneficial
[18]
for CLL cells as they receive proliferation and survival signals, which contribute to disease development .

Angiogenesis, the development of new vessels from pre-existing ones, is another feature associated to CLL
progression [19-21] . Increased angiogenesis has been observed in the bone marrow and lymph nodes of CLL
patients [22-24] . The microvessel density in the bone marrow positively correlates with the clinical stage of
CLL and has also been associated with a dysregulation of angiogenic factors . Additionally, increased
[22]
[25]
bone marrow angiogenesis in CLL has been suggested as a possible prognostic marker to determine the risk
of progression in early disease [26,27] .