CXCR4 mediates leukemic cell migration and survival in the testicular microenvironment

Abstract

The testis is the second most frequent extramedullary site of relapse in pediatric acute lymphoblastic leukemia (ALL). The mechanism for B‐cell (B) ALL cell migration towards and survival within the testis remains elusive. Here, we identified CXCL12–CXCR4 as the leading signaling axis for B‐ALL cell migration and survival in the testicular leukemic niche. We combined analysis of primary human ALL with a novel patient‐derived xenograft (PDX)‐ALL mouse model with testicular involvement. Prerequisites for leukemic cell infiltration in the testis were prepubertal age of the recipient mice, high surface expression of CXCR4 on PDX‐ALL cells, and CXCL12 secretion from the testicular stroma. Analysis of primary pediatric patient samples revealed that CXCR4 was the only chemokine receptor being robustly expressed on B‐ALL cells both at the time of diagnosis and relapse. In affected patient testes, leukemic cells localized within the interstitial space in close proximity to testicular macrophages. Mouse macrophages isolated from affected testes, in the PDX model, revealed a macrophage polarization towards a M2‐like phenotype in the presence of ALL cells. Therapeutically, blockade of CXCR4‐mediated functions using an anti‐CXCR4 antibody treatment completely abolished testicular infiltration of PDX‐ALL cells and strongly impaired the overall development of leukemia. Collectively, we identified a prepubertal condition together with high CXCR4 expression as factors affecting the leukemia permissive testicular microenvironment. We propose CXCR4 as a promising target for therapeutic prevention of testicular relapses in childhood B‐ALL. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Testicular dysfunction at diagnosis in children and teenagers with haematopoietic malignancies improves after initial chemotherapy

“…Testicular dysfunction may be due to gonadal infiltration by tumor cells and/or by the action of inflammatory cytokines on gonadal tissue. Indeed, testicular infiltration has been extensively described in boys with leukemia ( 31 – 33 ), and CXCL12 expressed in Sertoli cells has been identified as part of a paracrine signaling system with the potential to sustain the migration and persistence of leukemic cells in the testis ( 34 ). The coexistence of low FSH levels with Sertoli cells hypofunction could indicate a concomitant central hypogonadism in prepubertal boys, that is, a combined primary and central hypogonadism ( 24 ).…”

“…Testicular dysfunction may be due to gonadal infiltration by tumor cells and/or by the action of inflammatory cytokines on gonadal tissue. Indeed, testicular infiltration has been extensively described in boys with leukemia (31)(32)(33), and CXCL12 expressed in Sertoli cells has been identified as part of a paracrine signaling system with the potential to sustain the migration and persistence of leukemic cells in the testis (34). The coexistence of Comparison between serum hormone levels at diagnosis and after 3 months of chemotherapy in individual prepubertal boys with hematopoietic malignancies: standard/intermediate risk (SR/IR) and high risk (HR) acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL).…”

GPC-100, a novel CXCR4 antagonist, improves in vivo hematopoietic cell mobilization when combined with propranolol

“…In the PRESTO-TANGO β-arrestin assay [54], both GPC-100 and AMD3100 inhibited CXCL12 mediated recruitment of β-arrestin to CXCR4 with IC 50 values of 207 nM and 172 nM, respectively (Fig 3b). Directly relevant to stem cell mobilization, cell migration is a key phenotypic response upon CXCR4 activation [55][56][57]. For this assay, we used MM.1S (multiple myeloma) and U937 (acute myeloid leukemia) cells with high endogenous CXCR4 expression (S1 Table in S1 File, S1 Fig in S2 File) [58], which showed a robust migration response to CXCL12 with a sub-nanomolar EC 50 values (S2a, S2b Fig in S2 File).…”