Oncogene-independent BCR-like signaling adaptation confers drug resistance in Ph-like ALL

Hurtz, Christian; Wertheim, Gerald; Loftus, Joseph P.; Blumenthal, Daniel S.; Lehman, Anne W.; Li, Yong; Bagashev, Asen; Manning, Bryan; Cummins, Katherine D.; Burkhardt, Janis K.; Perl, Alexander E.; Carroll, Martin; Tasian, Sarah K.

doi:10.1172/jci134424

Cited by 33 publications

(35 citation statements)

References 66 publications

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“…Relatedly, phosphatidylinositol 3-kinase (PI3K) and SRC family kinases (LYN, LCK, SRC) were also identified in the downstream OCRs of several predicted OCNs in Ph-like ALL ( Figure 1C; Table S6). These findings collectively serve as unbiased support for our and others' prior pharmacologic studies that demonstrated effective targeting of JAK/STAT, PI3K, and SRC kinase pathway signaling in primary Ph-like ALL cells and preclinical models 15,19,25 . Importantly, OptiCon identified novel OCNs not previously known to be targets in Ph-like ALL, including BAG1 (BCL2associated athanogene 1), DUSP3 (dual specificity phosphatase 3), CD38, and NEK6 (never in mitosis gene A-related kinase 6); these genes have all been implicated in other leukemias or in tumorigenesis [26][27][28][29] .…”

Section: Network-controllability Analysis Of Patient Multi-omics Datasupporting

confidence: 75%

Network Analysis Reveals Synergistic Genetic Dependencies for Rational Combination Therapy in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia

Ding

Kim

Madden

et al. 2021

Preprint

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Systems biology approaches can identify critical targets in complex cancer signaling networks to inform therapy combinations and overcome conventional treatment resistance. Herein, we developed a data-driven, network controllability-based approach to identify synergistic key regulator targets in Philadelphia chromosome-like B-acute lymphoblastic leukemia (Ph-like B-ALL), a high-risk leukemia subtype associated with hyperactive signal transduction and chemoresistance. Integrated analysis of 1,046 childhood B-ALL cases identified 14 dysregulated network nodes in Ph-like ALL involved in aberrant JAK/STAT, Ras/MAPK, and apoptosis pathways and other critical processes. Consistent with network controllability theory, combination small molecule inhibitor therapy targeting a pair of key nodes shifted the transcriptomic state of Ph-like ALL cells to become less like kinase-activated BCR-ABL1-rearranged (Ph+) B-ALL and more similar to prognostically-favorable childhood B-ALL subtypes. Functional validation experiments further demonstrated enhanced anti-leukemia efficacy of combining the BCL-2 inhibitor venetoclax with tyrosine kinase inhibitors ruxolitinib or dasatinib in vitro in human Ph-like ALL cell lines and in vivo in multiple patient-derived xenograft models. Our study represents a broadly-applicable conceptual framework for combinatorial drug discovery, based on systematic interrogation of synergistic vulnerability pathways with pharmacologic targeted validation in sophisticated preclinical human leukemia models.

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Section: Network-controllability Analysis Of Patient Multi-omics Datasupporting

confidence: 75%

Network Analysis Reveals Synergistic Genetic Dependencies for Rational Combination Therapy in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia

Ding

Kim

Madden

et al. 2021

Preprint

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“…Surrogate markers to evaluate signaling pathway activation in patients with CRLF2 abnormalities and recurrent gene fusions It has been observed that in vitro TSLP stimulation of blasts carrying CRLF2 rearrangements or overexpression activates multiple signaling molecules, including Stat5, Erk, and Src [40]. In the context of B-ALL recurrent gene fusions, coexisting with CRLF2 abnormalities, we found phosphorylation of Stat5, CrkL and, Erk.…”

Section: Concurrence Of Crlf2 Abnormalities With B-all Gene Fusionsmentioning

confidence: 72%

“…Another plausible option is that BCR-ABL1 p190 protein, the most frequent isoform in ALL patients, contributes to the direct activation of CrkL, but also of Stat5 through Jak2 [41]. One BCR-ABL1 patient (L6) was negative for CrkL activation, and a possible explanation is that both CRLF2 overexpression and JAK2 mutation are required for phosphorylation of Stat5; unfortunately, the mutational status of JAK2 was not determined [40]. Our results suggest crosstalk and a synergistic effect between BCR-ABL1 and CRLF2 to activate the Jak2/Stat5 pathway [42,43], which could be prone to induce chemoresistance [18].…”

Section: Concurrence Of Crlf2 Abnormalities With B-all Gene Fusionsmentioning

confidence: 99%

CRLF2 and IKZF1 abnormalities in Mexican children with acute lymphoblastic leukemia and recurrent gene fusions: exploring surrogate markers of signaling pathways

Lorenzana

León

et al. 2021

The Journal of Pathology CR

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The gene fusions BCR‐ABL1, TCF3‐PBX1, and ETV6‐RUNX1 are recurrent in B‐cell acute lymphoblastic leukemia (B‐ALL) and are found with low frequency in coexistence with CRLF2 (cytokine receptor‐like factor 2) rearrangements and overexpression. There is limited information regarding the CRLF2 abnormalities and dominant‐negative IKZF1 isoforms associated with surrogate markers of Jak2, ABL, and Ras signaling pathways. To assess this, we evaluated 24 Mexican children with B‐ALL positive for recurrent gene fusions at diagnosis. We found CRLF2 rearrangements and/or overexpression, dominant‐negative IKZF1 isoforms, and surrogate phosphorylated markers of signaling pathways coexisting with recurrent gene fusions. All the BCR‐ABL1 patients expressed CRLF2 and were positive for pCrkl (ABL); most of them were also positive for pStat5 (Jak2/Stat5) and negative for pErk (Ras). TCF3‐PBX1 patients with CRLF2 abnormalities were positive for pStat5, most of them were also positive for pCrkl, and two patients were also positive for pErk. One patient with ETV6‐RUNX1 and intracellular CRLF2 protein expressed pCrkl. In some cases, the activated signaling pathways were reverted in vitro by specific inhibitors. We further analyzed a TCF3‐PBX1 patient at relapse, identifying a clone with the recurrent gene fusion, P2RY8‐CRLF2, rearrangement, and phosphorylation of the three surrogate markers that we studied. These results agree with the previous reports regarding resistance to treatment observed in patients with recurrent gene fusions and coexisting CRLF2 gene abnormalities. A marker phosphorylation signature was identified in BCR‐ABL1 and TCF3‐PBX1 patients. To obtain useful information for the assessment of treatment in B‐ALL patients with recurrent gene fusions, we suggest that they should be evaluated at diagnosis for CRLF2 gene abnormalities and dominant‐negative IKZF1 isoforms, in addition to the analyses of activation and inhibition of signaling pathways.

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“…The Ph-like subtype is BCR-ABL1 negative, but its gene expression feature is similar to that of BCR-ABL1-positive patients [89][90][91][92][93]. The Ph-like subtype was registered in the 2016 revision to the WHO classification of myeloid neoplasms and acute leukemia [19].…”

Section: Dux4 Mef2d and Znf384 Gene Fusionsmentioning

confidence: 99%

Emerging molecular subtypes and therapeutic targets in B-cell precursor acute lymphoblastic leukemia

Dai

et al. 2021

Front. Med.

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B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by genetic alterations with high heterogeneity. Precise subtypes with distinct genomic and/or gene expression patterns have been recently revealed using high-throughput sequencing technology. Most of these profiles are associated with recurrent non-overlapping rearrangements or hotspot point mutations that are analogous to the established subtypes, such as DUX4 rearrangements, MEF2D rearrangements, ZNF384/ZNF362 rearrangements, NUTM1 rearrangements, BCL2/MYC and/or BCL6 rearrangements, ETV6-RUNX1-like gene expression, PAX5alt (diverse PAX5 alterations, including rearrangements, intragenic amplifications, or mutations), and hotspot mutations PAX5 (p.Pro80Arg) with biallelic PAX5 alterations, IKZF1 (p.Asn159Tyr), and ZEB2 (p.His1038Arg). These molecular subtypes could be classified by gene expression patterns with RNA-seq technology. Refined molecular classification greatly improved the treatment strategy. Multiagent therapy regimens, including target inhibitors (e.g., imatinib), immunomodulators, monoclonal antibodies, and chimeric antigen receptor T-cell (CAR-T) therapy, are transforming the clinical practice from chemotherapy drugs to personalized medicine in the field of risk-directed disease management. We provide an update on our knowledge of emerging molecular subtypes and therapeutic targets in BCP-ALL.

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Oncogene-independent BCR-like signaling adaptation confers drug resistance in Ph-like ALL

Cited by 33 publications

References 66 publications

Network Analysis Reveals Synergistic Genetic Dependencies for Rational Combination Therapy in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia

Network Analysis Reveals Synergistic Genetic Dependencies for Rational Combination Therapy in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia

CRLF2 and IKZF1 abnormalities in Mexican children with acute lymphoblastic leukemia and recurrent gene fusions: exploring surrogate markers of signaling pathways

Emerging molecular subtypes and therapeutic targets in B-cell precursor acute lymphoblastic leukemia

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