Crosstalk between ROR1 and the Pre-B Cell Receptor Promotes Survival of t(1;19) Acute Lymphoblastic Leukemia

Abstract

SUMMARY We report that t(1;19)-ALL cells universally exhibit expression of and dependence on the cell surface receptor, ROR1. We further identify t(1;19)-ALL cell sensitivity to the kinase inhibitor dasatinib due to its inhibition of the pre-B-cell receptor (pre-BCR) signaling complex. These phenotypes are a consequence of developmental arrest at an intermediate/late stage of B-lineage maturation. Additionally, inhibition of pre-BCR signaling induces further ROR1 upregulation, and we identify distinct ROR1 and pre-BCR downstream signaling pathways that are modulated in a counter-balancing manner—both leading to AKT phosphorylation. Consistent with this, AKT phosphorylation is transiently eliminated after dasatinib treatment, but is partially restored following dasatinib potentiation of ROR1 expression. Consequently, ROR1 silencing accentuates dasatinib killing of t(1;19)-ALL cells.

Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

“…on April 18, 2017. by guest www.bloodjournal.org From responses were detected in both diagnostic and relapse samples from high-risk patients by MRD. Moreover, the IC 50 for dasatinib in these patients was at least tenfold lower than in any of the best BCP-ALL responders tested, including 5 ALL patients with rearranged TCF3-PBX1 (recently linked to active BCR signaling 19,46 ) who were sensitive to dasatinib but not imatinib ( Figure 6A). No known recurrent genetic abnormality could be linked to this phenotype (supplemental Table 3).…”

Idelalisib sensitivity and mechanisms of disease progression in relapsed TCF3-PBX1 acute lymphoblastic leukemia

“…4 The pre-B-cell receptor signaling pathway is activated in TCF3-PBX1 BCP-ALLs, and its inhibition has been identified as a promising approach for treating this disease. 1,5 With current treatment regimens, the prognosis in adult TCF3-PBX1 BCP-ALL patients is similar to that of other adult ALLs. 6 Most patients with TCF3-PBX1 BCP-ALL benefit from chemotherapy, however, the disease often recurs, at which point there are few effective treatment options.…”

“…4,5 The cells from the first Figure 1. Clinical timeline of TCF3-PBX1 BCP-ALL index patient 668 with treatment, sampling and analysis history.…”

Atomic force microscopy studies on cellular elastic and viscoelastic properties

“…However, if researchers are to better examine the role of cellular elastic and viscoelastic properties in vivo, primary cancer cells as well as their normal counterparts must be isolated for tests. Recent studies of primary cancerous B lymphocytes have shown that the receptor tyrosine kinase-like orphan receptor 1 (ROR1) is selectively expressed on the surface of B-cell chronic lymphocytic leukemia and on some B-cell lymphomas (including mantle cell lymphoma, marginal zone lymphoma, and follicular lymphoma), whereas normal B lymphocytes and other normal cells do not express ROR1 (Baskar et al, 2008;Bicocca et al, 2012). Hence, ROR1 is a suitable marker for isolating cancerous B lymphocytes from lymphoma patients.…”