Targeting of the deubiquitinase USP9X attenuates B-cell acute lymphoblastic leukemia cell survival and overcomes glucocorticoid resistance

Zhou, Mi; Wang, Ting; Lai, Hui‐Ling; Zhao, Xuejiao; Yu, Qin; Zhou, Jianfeng; Yang, Yang

doi:10.1016/j.bbrc.2015.02.115

Cited by 19 publications

(27 citation statements)

References 27 publications

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“…In keeping with the emerging functions of USP9X , its overexpression has been reported in B‐ALL, suggesting an oncogenic role . Knockdown of USP9X sensitises both prednisolone sensitive and resistant cell lines to glucocorticoid (GC)‐induced apoptosis, suggesting that reduced levels of USP9X may sensitise them to prednisolone treatment …”

Section: Discussionmentioning

confidence: 84%

“…The involvement of USP9X and DDX3X in cancer is known and another translocation involving USP9X has been reported in a BCR‐ABL1 ‐like ALL patient without CRLF2 ‐r . In keeping with the emerging functions of USP9X , its overexpression has been reported in B‐ALL, suggesting an oncogenic role . Knockdown of USP9X sensitises both prednisolone sensitive and resistant cell lines to glucocorticoid (GC)‐induced apoptosis, suggesting that reduced levels of USP9X may sensitise them to prednisolone treatment …”

Section: Discussionmentioning

confidence: 93%

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Characterisation of the genomic landscape of CRLF2‐rearranged acute lymphoblastic leukemia

Russell

Jones

Enshaei

et al. 2017

Genes Chromosomes & Cancer

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Deregulated expression of the type I cytokine receptor, CRLF2, is observed in 5–15% of precursor B‐cell acute lymphoblastic leukaemia (B‐ALL). We aimed to determine the clinical and genetic landscape of those with IGH‐CRLF2 or P2RY8‐CRLF2 (CRLF2‐r) using multiple genomic approaches. Clinical and demographic features of CRLF2‐r patients were characteristic of B‐ALL. Patients with IGH‐CRLF2 were older (14 y vs. 4 y, P < .001), while the incidence of CRLF2‐r among Down syndrome patients was high (50/161, 31%). CRLF2‐r co‐occurred with primary chromosomal rearrangements but the majority (111/161, 69%) had B‐other ALL. Copy number alteration (CNA) profiles were similar to B‐other ALL, although CRLF2‐r patients harbored higher frequencies of IKZF1 (60/138, 43% vs. 77/1351, 24%) and BTG1 deletions (20/138, 15% vs. 3/1351, 1%). There were significant differences in CNA profiles between IGH‐CRLF2 and P2RY8‐CRLF2 patients: IKZF1 (25/35, 71% vs. 36/108, 33%, P < .001), BTG1 (11/35, 31% vs. 10/108, 9%, P =.004), and ADD3 deletions (9/19, 47% vs. 5/38, 13%, P =.008). A novel gene fusion, USP9X‐DDX3X, was discovered in 10/54 (19%) of patients. Pathway analysis of the mutational profile revealed novel involvement for focal adhesion. Although the functional relevance of many of these abnormalities are unknown, they likely activate additional pathways, which may represent novel therapeutic targets.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 93%

Characterisation of the genomic landscape of CRLF2‐rearranged acute lymphoblastic leukemia

Russell

Jones

Enshaei

et al. 2017

Genes Chromosomes & Cancer

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“…Analysis of our cohort and publicly available databases revealed recurrent loss-of-function mutations in USP9X. This finding was surprising because USP9X is perceived mainly as an oncogene in solid tumors and in BCP-ALL and B-cell lymphoblastic lymphomas (37,40,51,52). Because USP9X is a deubiquitinase, its effect on tumor growth should largely be dependent on its substrates, which probably explains its ascribed role as tumor suppressor in pancreatic cancer (53).…”

Section: Discussionmentioning

confidence: 87%

“…USP9X is a deubquitinating enzyme that has been suggested to have a protumorigenic role by preventing the ubiquitinmediated degradation of prosurvival and growth proteins, such as MCL2 and ERG (37)(38)(39)(40). Furthermore, increased expression of USP9X was proposed to mediate resistance to glucocorticoids in ALL (40).…”

Section: Temporal Association Of Somatic Mutations Between Diagnosis Andmentioning

confidence: 99%

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Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

Schwartzman

Savino

Gombert

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Children with Down syndrome (DS) are prone to development of high-risk B-cell precursor ALL (DS-ALL), which differs genetically from most sporadic pediatric ALLs. Increased expression of cytokine receptor-like factor 2 (CRLF2), the receptor to thymic stromal lymphopoietin (TSLP), characterizes about half of DS-ALLs and also a subgroup of sporadic "Philadelphia-like" ALLs. To understand the pathogenesis of relapsed DS-ALL, we performed integrative genomic analysis of 25 matched diagnosis-remission and -relapse DSALLs. We found that the CRLF2 rearrangements are early events during DS-ALL evolution and generally stable between diagnoses and relapse. Secondary activating signaling events in the JAK-STAT/ RAS pathway were ubiquitous but highly redundant between diagnosis and relapse, suggesting that signaling is essential but that no specific mutations are "relapse driving." We further found that activated JAK2 may be naturally suppressed in 25% of CRLF2 pos DSALLs by loss-of-function aberrations in USP9X, a deubiquitinase previously shown to stabilize the activated phosphorylated JAK2. Interrogation of large ALL genomic databases extended our findings up to 25% of CRLF2 pos , Philadelphia-like ALLs. Pharmacological or genetic inhibition of USP9X, as well as treatment with low-dose ruxolitinib, enhanced the survival of pre-B ALL cells overexpressing mutated JAK2. Thus, somehow counterintuitive, we found that suppression of JAK-STAT "hypersignaling" may be beneficial to leukemic B-cell precursors. This finding and the reduction of JAK mutated clones at relapse suggest that the therapeutic effect of JAK specific inhibitors may be limited. Rather, combined signaling inhibitors or direct targeting of the TSLP receptor may be a useful therapeutic strategy for DS-ALL.C hildren with Down syndrome (DS) are at a markedly increased risk for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) (1). The poor survival of DS-ALL compared with ALL in children without DS ("sporadic" ALL) is related to increased treatment toxicity and to increased incidence of relapse (2). Thus, better therapy is needed for these patients.Previous studies by our group and others revealed differences between the genetics of DS-ALLs and of sporadic ALLs (3-6). The typical cytogenetic subgroups, ETV6-RUNX1 and hyperdiploid ALLs, are less common in DS-ALLs. Acquired somatic activation of the thymic stromal lymphopoietin (TSLP) pathway are present at diagnosis in about half of DS-ALLs. Aberrant expression of cytokine receptor-like factor 2 (CRLF2) in these leukemias is caused by chromosomal rearrangements consisting either of a microdeletion on chromosome X, juxtaposing the promoter of P2RY8 with the coding region of CRLF2, or by a translocation of CRLF2 into the Ig heavy chain (IgH) locus. CRLF2 heterodimerizes with IL7 receptor-α (IL7R) to form the receptor to TSLP (reviewed in ref. 7). TSLP receptors signal by activation of the JAK-STAT pathway. Interestingly, in the majority of DS-ALLs, SignificanceChildren with Down syndrome are at increased risk ...

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Notch Signaling and the Breast Cancer Microenvironment

Shen

Reedijk

2020

Advances in Experimental Medicine and Biology

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Notch promotes breast cancer progression through tumor initiating cell maintenance, tumor cell fate specification, proliferation, survival, and motility. In addition, Notch is recognized as a decisive mechanism in regulating various juxtacrine and paracrine communications in the tumor microenvironment (TME). In this chapter, we review recent studies on stress-mediated Notch activation within the TME and sequelae such as angiogenesis, extracellular matrix remodeling, changes in the innate and adaptive immunophenotype, and therapeutic perspectives.

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Targeting of the deubiquitinase USP9X attenuates B-cell acute lymphoblastic leukemia cell survival and overcomes glucocorticoid resistance

Cited by 19 publications

References 27 publications

Characterisation of the genomic landscape of CRLF2‐rearranged acute lymphoblastic leukemia

Characterisation of the genomic landscape of CRLF2‐rearranged acute lymphoblastic leukemia

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

Notch Signaling and the Breast Cancer Microenvironment

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