Tagged: Leukemia

Trending With Impact: Dual Requirement in Stem Cell Leukemia/Lymphoma

For the first time, researchers revealed the protein interactome, phospho-proteome and total proteome for the oncogenic fusion protein BCR-FGFR1.

Figure 6: Signaling pathways activated by BCR-FGFR1.
Figure 6: Signaling pathways activated by BCR-FGFR1.

The Trending With Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Oncotarget.com.

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Chromosomes are found in the nucleus of cells and consist of proteins and tightly coiled strands of DNA. During cell division, chromosomal translocations can occur while the chromosomes are being copied. This type of mutation can mean that an entire chromosome has moved to another location, or that a chromosome has broken, usually into two pieces, and moved to another site. Some translocations are harmless, but others can lead to aberrant cell proliferation and cancer.

“Over the last half century, chromosomal translocations encoding functional oncogenic proteins have been identified as drivers of multiple cancers, and account for 20% of all malignant neoplasms [1, 2].”

For example, the t(8;22)(p11;q11) chromosomal translocation leads to the initiation of an oncogenic fusion protein called the Breakpoint Cluster Region Fibroblast Growth Factor Receptor 1 (BCR-FGFR1). BCR-FGFR1 is a single driver of 8p11 myeloproliferative syndrome, which is also known as stem cell leukemia/lymphoma (SCLL).

“Stem cell leukemia/lymphoma (SCLL) exhibits distinct clinical and pathological features characterized by chromosomal translocations involving the FGFR1 gene at chromosome 8p11.”

In a trending new study, researchers from the University of California San Diego and Sanford Burnham Prebys Medical Discovery Institute examined mutations in PLCγ1 and Grb2 binding sites individually and when combined together in a double mutant within BCR-FGFR1. On May 11, 2022, the research paper was published in Oncotarget and entitled, “Proteomic analysis reveals dual requirement for Grb2 and PLCγ1 interactions for BCR-FGFR1-Driven 8p11 cell proliferation.”

The Study

In this study, the researchers used quantitative proteomic analyses to identify the crucial protein-to-protein interactions that may be necessary to activate BCR-FGFR1. The team used NIH3T3, HEK293T and 32D cells to assay five types of mutations: wild type BCR-FGFR1, a kinase-dead variant of BCR-FGFR1, a derivative of BCR-FGFR1 that contained a single mutation abolishing the Grb2 interaction site, a derivative of BCR-FGFR1 that contained a single mutation abolishing the PLCγ1 interaction site, and a double mutation that abolished both interaction sites (BCR(Y177F)-FGFR1(Y766F)).

“These data demonstrate that inhibition of either signaling pathway alone fails to inhibit hematopoietic cell proliferation, and demonstrate a dual requirement for Grb2 and PLCγ1 interactions with BCR-FGFR1 for proliferation.”

When either Grb2 or PLCγ1 signaling pathway was mutated, BCR-FGFR1 activity was decreased, but never abolished. However, when both Grb2 and PLCγ1 interactions were mutated, both cell transformation and proliferation were inhibited. The team demonstrated that BCR-FGFR1 dually relies on Grb2 and PLCγ1 for biological activity and the activation of cell signaling pathways. The researchers also found that the PLCγ1 inhibitor U73122 revealed that PLCγ1 is a potential therapeutic target for BCR-FGFR1-driven hematologic malignancies. In addition, the irreversible FGFR inhibitor futibatinib suppressed downstream signaling and cell transformation. 

“We demonstrate here that BCR-FGFR1 relies dually on the small adapter protein, Grb2, and the phospholipase, PLCγ1, for biological activity and the activation of cell signaling pathways (summarized in Figure 6).”

Figure 6: Signaling pathways activated by BCR-FGFR1.
Figure 6: Signaling pathways activated by BCR-FGFR1.

Conclusion

“Our work highlights the importance of sequencing based, mutation-specific therapies for FGFR1 induced hematologic malignancies.”

This study provides new insight into the potential molecular mechanisms underlying BCR-FGFR1 activity and identifies PLCγ1 as a therapeutic target for leukemia/lymphoma patients with this particular mutation. Future studies will be necessary to validate these findings in animal models and clinical trials. However, this study lays the groundwork for the development of new and more targeted leukemia/lymphoma therapies.

“These data unravel essential roles of Grb2 and PLCγ1 in BCR-FGFR1 mediated oncogenic growth and suggest the importance of further investigation into PLCγ1 as a potential therapeutic target in treating SCLL.”

Click here to read the full research paper published by Oncotarget.

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Trending with Impact: Acute Myeloid Leukemia and Midostaurin Response

Researchers examined midostaurin resistance or sensitivity in a cohort of patients with acute myeloid leukemia.

Figure 2: Differential gene expression for midostaurin sensitive vs. resistant samples identifies a unique signature.
Figure 2: Differential gene expression for midostaurin sensitive vs. resistant samples identifies a unique signature.

The Trending with Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Oncotarget.com.

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Acute myeloid leukemia (AML) is a heterogeneous malignancy that most commonly affects older adults, 60 years of age and older. NPM1, DNMT3A, and FLT3 are the most common genomic alterations found within this disease. In about 30% of AML patients, FLT3 is mutated. Midostaurin was the first FDA approved FLT3 inhibitor for AML. While Midostaurin has a successful overall survival benefit, both primary and secondary resistance remains common.

“A subtype of AML, classified by the presence of a FLT3-Internal Tandem Duplication (ITD) mutation, tends to have a worse prognosis with early relapse and death [5].”

Researchers from Oregon Health and Science University and Howard Hughes Medical Institute conducted a study to identify features that may predict response to midostaurin in FLT3 mutant and wild-type samples. They performed an ex vivo drug sensitivity screen on primary and relapsed AML samples, with corresponding targeted sequencing and RNA sequencing. The paper was entitled: “Genomic markers of midostaurin drug sensitivity in FLT3 mutated and FLT3 wild-type acute myeloid leukemia patients.”

The Study

In order to understand the impact that different genomic alterations have on midostaurin response, 214 patients were functionally assessed with midostaurin and their FLT3 status was annotated. Of these patients, the researcher identified 193 primary and 21 relapse AML samples from the Beat AML publicly available dataset. Risk groups within the cohort were as follows: 73 samples were favorable risk, 59 samples were intermediate, and 68 were adverse. The median age of patients in the cohort was 61, with 52% male and 48% female.

“We hypothesized that there are additional genomic alterations and gene expression changes outside of FLT3-ITD mutations that can influence AML sample resistance or sensitivity to midostaurin and aimed to further characterize these factors.”

Drug sensitivity screening, RNA sequencing/expression analysis, custom gene panel (GeneTrails) sequencing and variant detection, exome sequencing and variant detection, internal FLT3-ITD and NPM1 mutation detection, derivation of FLT3-ITD and NPM1 consensus calls, ex vivo functional drug screens, and statistical analysis were the methods used to observe the impact of genomic alterations on midostaurin response.

“Our research explored the multi-targeted nature of midostaurin and suggested a number of molecular mutational patterns that correlated with midostaurin drug sensitivity and resistance in both FLT3-ITD mutated and FLT3-ITD wild-type AML patient samples.”

Results

The researchers observed specific point mutations and gene expression patterns that they believe explain why there is a range of responses to midostaurin treatment. In the FLT3-ITD positive cohort, increased expression of the oncogene RGL4 (and regulator of the Ras-Raf-MEK-ERK cascade) correlated with poorer midostaurin response. In the FLT3-ITD negative cohort, KRAS mutations correlated with a poorer midostaurin response.

“We also observed that 16 / 34 of the most sensitive samples did not harbor a FLT3 mutation and a majority of differentially expressed genes were independent of FLT3 status.”

Conclusion

The authors point out that additional research studies will be needed given that their sample cohort was relatively small. They also note that since there are multiple FLT3 inhibitors available, it is important to understand the sensitivity mechanisms of each intervention in order to better personalize therapy for chemo-refractory or relapsed AML patients. 

“Overall, we identify genomic alterations that correlate with midostaurin response independent of FLT3-ITD status, propose that Ras-Raf-MEK-ERK inhibition in combination therapy could limit resistance to midostaurin, and suggest that within the overall AML population there may be therapeutic benefit of midostaurin in patients with certain expression profiles.”

Click here to read the full scientific study, published in Oncotarget.

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Oncotarget is a proud participant of the AACR Annual Meeting 2021 #AACR21