Phase II/III trial of a pre-transplant farnesyl transferase inhibitor in juvenile myelomonocytic leukemia: a report from the Children's Oncology Group.

BACKGROUND: Juvenile myelomonocytic leukemia (JMML) is not durably responsive to chemotherapy, and approximately 50% of patients relapse after hematopoietic stem cell transplant (HSCT). Here we report the activity and acute toxicity of the farnesyl transferase inhibitor tipifarnib, the response rate to 13-cis retinoic acid (CRA) in combination with cytoreductive chemotherapy, and survival following HSCT in children with JMML. PROCEDURE: Eighty-five patients with newly diagnosed JMML were enrolled on AAML0122 between 2001 and 2006. Forty-seven consented to receive tipifarnib in a phase II window before proceeding to a phase III trial of CRA in combination with fludarabine and cytarabine followed by HSCT and maintenance CRA. Thirty-eight patients enrolled only in the phase III trial. RESULTS: Overall response rate was 51% after tipifarnib and 68% after fludarabine/cytarabine/CRA. Tipifarnib did not increase pre-transplant toxicities. Forty-six percent of the 44 patients who received protocol compliant HSCT relapsed. Five-year overall survival was 55 ± 11% and event-free survival was 41 ± 11%, with no significant difference between patients who did or did not receive tipifarnib. CONCLUSIONS: Administration of tipifarnib in the window setting followed by HSCT in patients with newly diagnosed JMML was safe and yielded a 51% initial response rate as a single agent, but failed to reduce relapse rates or improve long-term overall survival.

Comparative distributions of pituitary adenylyl cyclase-activating polypeptide and its selective type I receptor mRNA in the frog (Xenopus laevis) brain.

The detailed mRNA distributions of pituitary adenylyl cyclase-activating polypeptide (PACAP) and its selective type I receptor (PAC(1)) were systematically compared in the brain of the frog Xenopus laevis. PACAP mRNA expression overlapped with that of PAC(1) in many brain areas such as the pallium, hypothalamic preoptic area, ventral hypothalamic nuclei, habenular nucleus, most thalamic nuclei, the cerebellular nucleus, and nuclei of isthmi. In some structures, PACAP and PAC(1) gene transcripts were present in anatomically distinct cell layers. For example, in the olfactory bulb, PACAP mRNA was present in the mitral cell layer, whereas gene transcripts for the receptor were observed in the granule layer. In a number of regions, expression showed no obvious overlap. PAC(1) but not PACAP mRNA was present at moderate levels in the Purkinje cell layer of the cerebellum and distal lobe of the pituitary. Conversely, PAC(1) gene expression was absent in the spinal cord while PACAP mRNA signals were observed in the medial portion of the ventral horn and deep portion of the dorsal horn. The granule and molecular cell layer of the cerebellum, alpha-motor neurons in the spinal cord, and reticular nucleus of isthmi showed neither PACAP nor PAC(1) gene transcripts. These localized patterns of ligand and receptor gene expression suggest possible PACAP projection and target fields in the frog brain.

Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis.

The PTPN11 gene encodes SHP-2 (Src homology 2 domain-containing protein tyrosine Phosphatase), a nonreceptor tyrosine protein tyrosine phosphatase (PTPase) that relays signals from activated growth factor receptors to p21Ras (Ras) and other signaling molecules. Mutations in PTPN11 cause Noonan syndrome (NS), a developmental disorder characterized by cardiac and skeletal defects. NS is also associated with a spectrum of hematologic disorders, including juvenile myelomonocytic leukemia (JMML). To test the hypothesis that PTPN11 mutations might contribute to myeloid leukemogenesis, we screened the entire coding region for mutations in 51 JMML specimens and in selected exons from 60 patients with other myeloid malignancies. Missense mutations in PTPN11 were detected in 16 of 49 JMML specimens from patients without NS, but they were less common in other myeloid malignancies. RAS, NF1, and PTPN11 mutations are largely mutually exclusive in JMML, which suggests that mutant SHP-2 proteins deregulate myeloid growth through Ras. However, although Ba/F3 cells engineered to express leukemia-associated SHP-2 proteins cells showed enhanced growth factor-independent survival, biochemical analysis failed to demonstrate hyperactivation of the Ras effectors extracellular-regulated kinase (ERK) or Akt. We conclude that SHP-2 is an important cellular PTPase that is mutated in myeloid malignancies. Further investigation is required to clarify how these mutant proteins interact with Ras and other effectors to deregulate myeloid growth.