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Bones provide both skeletal scaffolding and space for hematopoiesis in its marrow. Previous work has shown that these functions were tightly regulated by the nervous system. The central and peripheral nervous systems tightly regulate compact bone remodeling, its metabolism, and hematopoietic homeostasis in the bone marrow (BM). Accumulating evidence indicates that the nervous system, which fine-tunes inflammatory responses and alterations in neural functions, may regulate autoimmune diseases. Neural signals also influence the progression of hematological malignancies such as acute and chronic myeloid leukemias. Here, we review the interplay of the nervous system with bone, BM, and immunity, and discuss future challenges to target hematological diseases through modulation of activity of the nervous system.

Purpose of Review Although tyrosine kinase inhibitors (TKIs) spectacularly improve the disease burden and the overall survival of chronic myeloid leukemia patients, early identification of a subset of poor TKI responders has been recognized as a critical goal to prevent disease progression in these patients. We herein review the past and recent evidence on the impact of early response. Recent Findings In the recent years, the achievement of an early molecular response (EMR, defined as 3-month BCR-ABL1 transcript

Ninety-one previously untreated patients with chronic myeloid leukemia admitted to three Stockholm hospitals 1973-1978 were studied. There were 49 men and 42 women with a mean age of 56 years (range 15-93). Sixty-five patients were Philadelphia chromosome (Ph1) positive and 17 were Ph1 negative (mean age 51 and 70 years, respectively). After a mean observation time of 5.2 years, 64 patients had deceased, 45 of them in blast transformation. A low hemoglobin value and a high total blast cell count at diagnosis were associated with a poor prognosis in the Ph1 positive group. Other routine clinical and laboratory variables were of subordinate prognostic importance. Early splenectomy in 15 Ph1 positive patients did not improve survival. Median survival from diagnosis was 38 months for Ph1 positive patients as compared to 12 months for the Ph1 negative group.

Context.—Mast cells may be increased as a reactive mastocytosis in various hematologic disorders and malignant neoplasms, as well as in systemic mast cell disease (SMCD). There are no statistical differences in mast cell numbers in reactive mastocytosis and SMCD; however, SMCD usually reveals dyspoietic mast cells and other dyspoietic bone marrow elements. In addition, SMCD is frequently (45%) associated with myeloproliferative disorders (MPDs) (17%) and myelodysplastic syndromes (MDSs) (28%). Thus, it has been suggested that SMCD may represent one aspect of a hematologic disorder that involves multiple bone marrow lineages. Objective.—To perform a systematic evaluation of MPDs and MDSs without SMCD for dyspoietic mast cells. Design.—A total of 55 MPDs or MDSs were reviewed, including 20 cytogenetically proven chronic myeloid leukemias, 6 essential thrombocythemias, 2 polycythemia veras, 21 cytogenetically proven MDSs, and 6 chronic myelomonocytic leukemias. Cases of idiopathic myelofibrosis were not included due to lack of spicules. The bone marrow aspirates were reviewed for an increase in mast cells (1+ to 3+), dyspoietic features within mast cells (decreased cytoplasmic granularity, uneven granule distribution), and a predominance of fusiform mast cells. Results.—All cases, except 2 MDSs, had evaluable bone marrow spicules. Of interest, the MPDs were significantly more associated with increased and dyspoietic mast cells (57% and 61%, respectively) than were the MDSs (11% and 4%, respectively). The 2 polycythemia veras and 6 chronic myelomonocytic leukemias did not reveal increased or dyspoietic mast cells. Conclusions.—These findings indicate that MPDs (chronic myeloid leukemia and essential thrombocythemia) frequently contain neoplastic mast cells as the spectrum of abnormal bone marrow cells. This feature, in conjunction with other parameters, may possibly be useful in the differential diagnosis of MPDs and MDSs. Our findings, compared with the previously reported findings in SMCD, suggest that SMCD may be more closely related to MPDs than to MDSs.

The manifestations, diagnosis and management of the rarer chronic myeloid leukemias are reviewed, with special attention to problems that affect elderly patients. The spectrum of disorders includes atypical myeloproliferative syndrome, so-called Ph-negative CGL, chronic myelomonocytic leukemia, and leukemias characterized by chronic proliferation of neutrophil, eosinophil, or basophil leukocytes. These latter are sometimes difficult to differentiate from chronic nonleukemic proliferations of the index cells. Termination in an acute myeloid leukaemia that is usually refractory to treatment may occur in any of the above disorders but is not a constant event.

In this issue of Blood , Gambacorti-Passerini et al describe, for the first time, mutations of an ethanolamine kinase called ETNK1, which is physiologically involved in the first step of the phosphatidylethanolamine biosynthesis pathway. 1 The authors describe 2 recurrent point mutations of ETNK1 in 9% of atypical chronic myeloid leukemias (aCMLs) and show that these mutations are associated with the impaired catalytic activity of the kinase.

The paper discusses certain distributive and clustering modes of stimulus P and of its receptors. When combined with topologic features peculiar to sources and stem cells, these parameters account not only for the cycling variations typical of normal stem cells but also for seemingly paradoxical shifts in proliferative activity of cells grafted into patients with chronic myeloid leukemias.

Note: An isochromosome 17 results in a loss of the short arm (17p) and duplication of the long arm (17q) leading to a single copy of 17p and three copies of 17q. An i(17q), usually observed in a complex karyotype, has been reported in solid tumors and in various types of hematological diseases: acute and chronic myeloid leukemias, acute lymphoid leukemiasand chronic lymphoid leukemias, and Hodgkin and non-Hodgkin lymphomas. In chronic myeloid leukemia, i(17q) is a frequent and well known secondary anomaly, either solely in 10% of cases, or with other additional anomalies, in at least another 10% of cases, in particular with +8.

Antigen-presenting capability and expression of HLA-II antigens on peripheral blood monocytes were analyzed by isotope incorporation technique and indirect immunofluorescence assay with monoclonal antibodies Tü 22, Tü 36 and anti-Leu-M2 in patients with acute and chronic myeloid leukemias (AML, CML). All patients (17 AML and 13 CML) demonstrated impaired antigen-presenting capability of monocytes (P0.001), when compared with simultaneously studied controls, which were HLA-identical normal siblings of the patients. These patients also showed a markedly decreased proportion of MAC-120- and HLA-DQ-positive monocytes as compared with the controls (P0.001), while the percentage of HLA-DR-positive monocytes in the patients was similar to that observed in the controls (P0.05). These findings suggested, therefore, that impaired antigen-presenting capability of monocytes correlated with their decreased expression of HLA-DQ in patients with acute and chronic myeloid leukemias.

Using a sensitive radioimmunoassay,we detected human immunoreactive calcitonin in cell extracts and in cell-exposed media of the HL60 cell line derived originally from a patient with acute promyelocytic leukemia. The cell extract was chromatographed on a reverse-phase high- pressure liquid chromatography system. Radioimmunoassay of the fractions showed that the immunoreactive calcitonin was heterogeneous but had peaks corresponding to those of synthetic human calcitonin monomer and its sulphoxide. We have previously shown that levels of immunoreactive calcitonin are elevated in the plasma of the majority of patients with acute and chronic myeloid leukemias. Our studies with the HL60 cell line add further support to the concept that leukemic cells can synthesize immunoreactive calcitonin “ectopically.”

Isozymes of amino acid naphthylamidase (called B and C) with deviating electrophoretic mobilities were found in peripheral blood leukocytes of 25 out of 25 untreated acute and chronic myeloid leukemias (AML and CML) and in 2 out of 2 cases of idiopathic myelofibrosis, while a normal pattern was found in 3 control groups and 5 cases of polycythemia vera. In the AML group, a correlation between electrophoretic mobility and the number of blast cells was found, and on remission, the B isozyme mobility was nearly normalized. Thus, deviating electrophoretic mobility of the B isozyme seemed to be valuable for diagnosis of myeloid leukemias, and in the AML group, the change in mobility might indicate the size of the leukemic clone.