Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency

Sachs, Zohar; Been, Raha A.; DeCoursin, Krista J.; Nguyen, Hanh T.; Hassan, Nurul Azyan Mohd; Noble-Orcutt, Klara E.; Eckfeldt, Craig E.; Pomeroy, Emily J.; Díaz-Flores, Ernesto; Geurts, Jennifer L.; Diers, Miechaleen D.; Hasz, Diane E.; Morgan, Kelly; MacMillan, Margaret L.; Shannon, Kevin; Largaespada, David A.; Wiesner, Stephen M.

doi:10.3324/haematol.2015.136002

Cited by 16 publications

(12 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 42 A preclinical study demonstrated prolonged animal survival in NF1 -deficient MPN mice treated with ruxolitinib, as well as reduced colony formation of primary KRAS -mutant JMML cells plated in vitro with ruxolitinib. 43 In our prior work, however, we observed minimal inhibition of JAK/STAT signaling in PTPN11 -mutant JMML iPSC-derived cells treated with ruxolitinib. 18 …”

Section: Discussionmentioning

confidence: 71%

Mutation-specific signaling profiles and kinase inhibitor sensitivities of juvenile myelomonocytic leukemia revealed by induced pluripotent stem cells

et al. 2018

View full text Add to dashboard Cite

Juvenile myelomonocytic leukemia (JMML) is an uncommon myeloproliferative neoplasm driven by Ras pathway mutations and hyperactive Ras/MAPK signaling. Outcomes for many children with JMML remain dismal with current standard-of-care cytoreductive chemotherapy and hematopoietic stem cell transplantation. We used patient-derived induced pluripotent stem cells (iPSCs) to characterize the signaling profiles and potential therapeutic vulnerabilities of PTPN11-mutant and CBL-mutant JMML. We assessed whether MEK, JAK, and PI3K/mTOR kinase inhibitors (i) could inhibit myeloproliferation and aberrant signaling in iPSC-derived hematopoietic progenitors with PTPN11 E76K or CBL Y371H mutations. We detected constitutive Ras/MAPK and PI3K/mTOR signaling in PTPN11 and CBL iPSC-derived myeloid cells. Activated signaling and growth of PTPN11 iPSCs were preferentially inhibited in vitro by the MEKi PD0325901 and trametinib. Conversely, JAK/STAT signaling was selectively activated in CBL iPSCs and abrogated by the JAKi momelotinib and ruxolitinib. The PI3Kδi idelalisib and mTORi rapamycin inhibited signaling and myeloproliferation in both PTPN11 and CBL iPSCs. These findings demonstrate differential sensitivity of PTPN11 iPSCs to MEKi and of CBL iPSCs to JAKi, but similar sensitivity to PI3Ki and mTORi. Clinical investigation of mutation-specific kinase inhibitor therapies in children with JMML may be warranted.

show abstract

Section: Discussionmentioning

confidence: 71%

Mutation-specific signaling profiles and kinase inhibitor sensitivities of juvenile myelomonocytic leukemia revealed by induced pluripotent stem cells

et al. 2018

View full text Add to dashboard Cite

show abstract

“…In their report, the median age at the symptom onset was 3.5 years ( 9 ). In another report, mononuclear cells of mice treated with ruxolitinib showed a trend toward a reduced phosphor-STAT5 induction in response to in vitro GM-CSF stimulation, although this trend was not statistically significant ( 10 ). In the present case, an onset of two years from the start of ruxolitinib treatment seems to be reasonable based on the immunological abnormality of PMF.…”

Section: Discussionmentioning

confidence: 99%

Secondary Pulmonary Alveolar Proteinosis Associated with Primary Myelofibrosis and Ruxolitinib Treatment: An Autopsy Case

et al. 2020

View full text Add to dashboard Cite

Pulmonary alveolar proteinosis (PAP) is an uncommon lung disorder characterized by the excessive accumulation of surfactant-derived lipoproteins in the pulmonary alveoli and terminal bronchiole. Secondary PAP associated with primary myelofibrosis (PMF) is extremely rare, and to our knowledge, no autopsy case has been reported. We herein report an autopsy case of secondary PAP occurring in a patient with PMF who was treated with the Janus kinase 1/2 inhibitor ruxolitinib. We confirmed a diagnosis of PAP with complications based on the pathological findings at the autopsy. Notably, this case might suggest an association between ruxolitinib treatment and PAP occurrence.

show abstract

“…As a Janus kinase (JAK)1/2 inhibitor, ruxolitinib was also useful in haematological malignancies with RAS pathway hyperactivation because ruxolitinib could reduce STAT5 activation. 17,18 STAT5 is important to maintain the overactivated RAS pathway, and ruxolitinib could reverse the expansion of immature myeloid cells and decrease autonomous colony-forming unit-granulocyte -macrophage formation to alleviate symptoms and reduce the spleen size by reducing STAT5 activation. 17,18 Furthermore, previous research demonstrated that ruxolitinib markedly reduced the tumour cell proliferation of KRAS-mutated mice and decreased the KRAS activation gene signature.…”

Section: Discussionmentioning

confidence: 99%

<p>Ruxolitinib Plus Decitabine Effectively Treats Myelodysplastic Syndrome/Myeloproliferative Neoplasm, Unclassifiable, by Decreasing the Variant Allele Frequency of <em>KRAS</em></p>

Luo

et al. 2020

OTT

View full text Add to dashboard Cite

Myelodysplastic syndrome/myeloproliferative neoplasm, unclassifiable (MDS/ MPN-U) is a subtype of MDS/MPN that exhibits a combination of the features of both MDS and MPN. To date, no curative treatment is available for MDS/MPN-U; however, previous studies have suggested a potential survival advantage for ruxolitinib and hypomethylating agents. We reported a case of a JAK2-negative but KRAS-positive MDS/MPN-U patient treated with ruxolitinib plus decitabine. After treatment, the patient's clinical symptoms were moderated, and the size of the spleen and the peripheral blood cell counts were reduced. These effects might be due to the regimen's ability to reduce STAT5 activation and upregulate microRNA-181c to downregulate the variant allele frequency (VAF) of KRAS.

show abstract

Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency

Cited by 16 publications

References 70 publications

Mutation-specific signaling profiles and kinase inhibitor sensitivities of juvenile myelomonocytic leukemia revealed by induced pluripotent stem cells

Mutation-specific signaling profiles and kinase inhibitor sensitivities of juvenile myelomonocytic leukemia revealed by induced pluripotent stem cells

Secondary Pulmonary Alveolar Proteinosis Associated with Primary Myelofibrosis and Ruxolitinib Treatment: An Autopsy Case

<p>Ruxolitinib Plus Decitabine Effectively Treats Myelodysplastic Syndrome/Myeloproliferative Neoplasm, Unclassifiable, by Decreasing the Variant Allele Frequency of <em>KRAS</em></p>

Contact Info

Product

Resources

About