Genetic adaptation to extreme hypoxia: study of high-altitude pulmonary edema in a three-generation Han Chinese family.

Organismal response to hypoxia is essential for critical regulation of erythropoiesis, other physiological functions, and survival. There is evidence of individual variation in response to hypoxia as some but not all of the affected individuals develop polycythemia, and or pulmonary and cerebral edema. A significant population difference in response to hypoxia exist as many highland Tibetan, Ethiopian, and Andean natives developed adaptive mechanisms to extreme hypoxia. A proportion of non-adapted individuals exposed to high altitude develop pulmonary edema (HAPE), pulmonary hypertension, cerebral edema, and extreme polycythemia. The isolation of causative gene(s) responsible for HAPE and other extreme hypoxia complications would provide a rational basis for specific targeted therapy of HAPE, allow its targeted prevention for at-risk populations, and clarify the pathophysiology of other hypoxic maladaptations. The only suggested genetic linkage among unrelated individuals with HAPE has been with endothelial nitric oxide synthase (eNOS) gene. Here we describe a family with multiple members affected with HAPE in three generations. Families with multiple affected members with HAPE have not been described. We first ruled out linkage of HAPE with the eNOS gene. We then performed an analysis of the whole genome using high-density SNP arrays (Affymetrix v5.0) and, assuming a single gene causation of HAPE, ruled out linkage with 34 other candidate genes. Only the HIF2A haplotype was shared by individuals who exhibit the HAPE phenotype, and work on its possible causative role in HAPE is in progress. The small size of our family does not provide sufficient power for a conclusive analysis of linkage. We hope that collaboration with other investigators with access to more HAPE patients will lead to the identification of gene(s) responsible for HAPE and possibly other maladaptive hypoxic complications.

Molecular and phenotypic analysis of Philadelphia chromosome-positive bilineage leukemia: possibility of a lineage switch from T-lymphoid leukemic progenitor to myeloid cells.

The occurrence of acute bilineage leukemia is thought to be the malignant transformation of a myeloid or lymphoid leukemic progenitor with the potential to differentiate into the other lineages; however, the mechanisms of this lineage switch are not well understood. Here, we report on the extremely rare case of adult Philadelphia chromosome-positive acute bilineage leukemia, which is characterized by T-cell acute lymphoblastic leukemia and acute myelomonocytic leukemia. Chromosome analysis showed 46,XY,del(7)(p11.2),t(9;22)(q34;q11.2) in all metaphases and a minor BCR/ABL chimeric gene was detected in these leukemic cells by PT-PCR. When the CD5+ and CD5- cells were sorted, a fusion gene of BCR/ABL and the same clonally rearranged band of a T-cell receptor (TCR) gene were detected in both populations. Nucleotide sequencing of the TCR-gamma gene revealed the clonal rearrangement of the V8-JGT2 complex in both populations. Overexpression of PU.1, which plays a fundamental role in myelomonocyte development, was found in the sorted CD34+CD7+ and CD5-, but not CD5+ cells. These results suggest that leukemic progenitor cells in the T-lineage with the del(7) and t(9;22) have the potential to differentiate into myeloid lineage, and that enforced PU.1 expression may contribute in part of this phenomenon.

Upregulated production of IL-6, but not IL-10, by interferon-alpha induces SOCS3 expression and attenuates STAT1 phosphorylation in myeloma cells.

Interferon-alpha (IFN-alpha) is used as a treatment for multiple myeloma, although its clinical effects remain controversial. Here, we investigated whether IFN-alpha altered the autocrine production of interleukin-6 (IL-6) or IL-10, both identified as key cytokines regulating myeloma cell growth/survival, and found that IL-6, but not IL-10, induced by IFN-alpha attenuated IFN-alpha-mediated signaling in myeloma cells via an upregulated SOCS3. Using reverse transcription-polymerase chain reaction, expression of the IL-6 gene (IL-6) and IL-10 was detected in two and three of eight myeloma cell lines, respectively. When myeloma cells were cultured with IFN-alpha, an increase of IL-6 and IL-10 production was detected in IL-6-expressing and in IL-10-expressing cells, respectively. IFN-alpha inhibited the cell growth of these myeloma lines. Addition of an IL-6-neutralizing antibody prolonged the phosphorylation of STAT1 induced by IFN-alpha and significantly enhanced the cell growth suppression of IFN-alpha on IL-6-expressing cells. However, a similar blocking of IL-10 in the presence of IFN-alpha did not affect the growth/survival of IL-10-expressing cells. Interestingly, exogenous IL-6, but not IL-10, induced high levels of SOCS3 expression. Although upregulation of SOCS3 was also observed in the presence of IFN-alpha alone in IL-6-expressing cells, this expression was completely abrogated by the IL-6-neutralizing antibody. The L929 cell line transfected with SOCS3 showed the protection from the growth suppression of IFN-alpha. These results suggest that IL-6 induced by IFN-alpha plays an important role in the growth/survival of myeloma cells via an autocrine loop, and upregulated SOCS3 by IL-6 may be at least partially responsible for the IL-6-mediated inhibition of IFN-alpha signaling in myeloma cells.

Acute myeloid leukemia with t(8;21)(q22;q22) manifesting as granulocytic sarcomas in the rhinopharynx and external acoustic meatus at relapse after high-dose cytarabine: case report and review of the literature.

We report a 31-year-old female with t(8;21)(q22;q22) acute myeloid leukemia (AML), M2 in the FAB classification. Complete remission was achieved with daunorubicin and cytarabine induction therapy followed by three courses of high-dose cytarabine consolidation. Only 3 months later, the patient relapsed with granulocytic sarcomas (GSs) in her rhinopharynx, external acoustic meatus, and bone marrow. She received focal radiation for the GSs and successfully underwent reinduction chemotherapy. Subsequently, she received a matched related donor peripheral blood stem cell transplantation followed by high-dose chemotherapy and is now in a second remission. We summarized 79 reported cases of t(8;21) AML with GS and reviewed the literature to identify differences in the characteristics of t(8;21) AML with GS between adults and children. To our knowledge, this is the first report of pharyngeal GS in t(8;21) AML, and focal irradiation plus more intensive postinduction therapy during first remission, such as allogeneic-SCT, may be effective in adult t(8;21) AML patients with GS.