SHP1 loss augments DLBCL cellular response to ibrutinib: a candidate predictive biomarker.

SHP1, a tyrosine phosphatase, negatively regulates B-cell receptor (BCR) signaling. Ibrutinib selectively inhibits BTK and has been approved for the treatment of several types of B-cell lymphomas, but not yet in diffuse large B-cell lymphoma (DLBCL). A phase 3 clinical trial of ibrutinib-containing regimen has been completed to evaluate its activity in subtypes or subsets of DLBCL patients. Although the subtype of activated B-cell like (ABC) DLBCL is characterized by chronic active BCR signaling, only a fraction of ABC-DLBCL patients seem to benefit from ibrutinib-containing regimen. New alternative predictive biomarkers are needed to identify patients who better respond. We investigated if SHP1 plays a role in defining the level of the BCR activity and impacts the response to ibrutinib. A meta-analysis revealed that lack of SHP1 protein expression as well as SHP1 promoter hypermethylation is strongly associated with NHL including DLBCL. On a tissue microarray of 95 DLBCL samples, no substantial difference in SHP1 expression was found between the GCB and non-GCB subtypes of DLBCL. However, we identified a strong reverse correlation between SHP1 expression and promoter methylation suggesting that promoter hypermethylation is responsible for SHP1 loss. SHP1 knockout in BCR-dependent GCB and ABC cell lines increased BCR signaling activities and sensitize lymphoma cells to the action of ibrutinib. Rescue of SHP1 in the knockout clones, on the other hand, restored BCR signaling and ibrutinib resistance. Further, pharmacological inhibition of SHP1 in both cell lines and patient-derived primary cells demonstrate that SHP1 inhibition synergized with ibrutinib in suppressing tumor cell growth. Thus, SHP1 loss may serve as an alternative biomarker to cell-of-origin to identify patients who potentially benefit from ibrutinib treatment. Our results further suggest that reducing SHP1 pharmacologically may represent a new strategy to augment tumor response to BCR-directed therapies. Schematic diagram summarizing the major findings. Left panel. When SHP1 is present and functional, it negatively regulates the activity of the BCR pathway. Right pane. When SHP1 is diminished or lost, cells depend more on the increased BCR signaling and making them vulnerable to BTK inhibitor, ibrutinib. Diagram was generated using BioRender.

Effects of Interim Assessments Across the Achievement Distribution: Evidence From an Experiment.

We use data from a large-scale experiment conducted in Indiana in 2009-2010 to examine the impact of two interim assessment programs (mCLASS and Acuity) across the mathematics and reading achievement distributions. Specifically, we focus on whether the use of interim assessments has a particularly strong effect on improving outcomes for low achievers. Quantile regression is used to estimate treatment effects across the entire achievement distribution (i.e., provide estimates in the lower, middle, or upper tails). Results indicate that in Grades 3 to 8 (particularly third, fifth, and sixth) lower achievers seem to benefit more from interim assessments than higher achieving students.

Simple multiplex RT-PCR for identifying common fusion BCR-ABL transcript types and evaluation of molecular response of the a2b2 and a2b3 transcripts to Imatinib resistance in north Indian chronic myeloid leukemia patients.

INTRODUCTION: Chronic myeloid leukemia (CML) is characterized by the Philadelphia chromosome, an abnormally shortened chromosome 22. It is the result of a reciprocal translocation of chromosomes 9 and 22, creating BCR-ABL fusion transcripts, b3a2, b2a2, and e1a2. The aim of our study was to determine the type of BCR-ABL fusion transcripts for molecular diagnosis and investigate the frequency of BCR-ABL fusion transcripts in CML patients by multiplex RT-PCR in CML. MATERIALS AND METHODS: A single reaction with multiple primers multiplex PCR was used to detect and investigate the type and frequency in 200 CML patients among which 116, 33, and 51 were in CP, AP, and BC phase, respectively. RESULTS: The study included 200 CML patients, among whom breakpoints in b3a2, b2a2 transcripts were detected in 68% and 24%, respectively, while 8% of the patients showed both b3a2/b2a2. A statistically significant difference was seen between frequency of BCR-ABL fusion transcripts and gender (P = 0.03), molecular response (P = 0.04), and hematological response (P = 0.05). However, there was no correlation found between frequencies of BCR-/ABL fusion transcripts and other clinicopathological parameters like age, type of therapy, thrombocytopenia, and white blood cell count. CONCLUSION: Multiplex reverse transcriptase-polymerase chain reaction is useful and saves time in the detection of BCR-ABL variants; the occurrence of these transcripts associated with CML can assist in prognosis and treatment of disease.