Jun Mo

Rho GTPase Cdc42 coordinates hematopoietic stem cell quiescence and niche interaction in the bone marrow

Adult hematopoietic stem cells (HSCs) exist in a relatively quiescent state in the bone marrow (BM) microenvironment to fulfill long-term self-renewal and multilineage differentiation functions, an event that is tightly regulated by extrinsic and intrinsic cues. However, the mechanism coordinating the quiescent state of HSCs and their retention in the BM microenvironment remains poorly understood. In a conditional-knockout mouse model, we show that Cdc42−/− HSCs enter the active cell cycle, resulting in significantly increased number and frequency of the stem/progenitor cells in the BM. Cdc42 deficiency also causes impaired adhesion, homing, lodging, and retention of HSCs, leading to massive egress of HSCs from BM to distal organs and peripheral blood and to an engraftment failure. These effects are intrinsic to the HSCs and are associated with deregulated c-Myc, p21Cip1, β1-integrin, and N-cadherin expressions and defective actin organization. Thus, Cdc42 is a critical coordinator of HSC quiescence maintenance and interaction with the BM niche.

Chemotherapy for Myeloid Malignancy in Children With Fanconi Anemia

Children with Fanconi anemia (FA) have a markedly increased risk of developing myeloid malignancies. Historically, patients with FA and myeloid malignancy have extremely poor outcomes. There are currently no clinical trials or case series addressing the use of chemotherapy for children with FA, except in the context of preparative regimens for stem cell transplantation (SCT). In this report we describe the toxicity of a chemotherapy approach for patients with FA and myeloid malignancy to achieve cytoreduction prior to SCT.

Numerical chromosomal changes and risk of development of myelodysplastic syndrome–acute myeloid leukemia in patients with Fanconi anemia

Fanconi Anemia (FA) is an inherited bone marrow failure syndrome characterized by congenital abnormalities, progressive marrow failure and predisposition to myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and solid tumors. The most common acquired chromosomal aberrations in FA patients are trisomy of 1q and monosomy of chromosome 7; the latter is known to be associated with poor prognosis. A few reports also suggest that gains of 3q are associated with progression to MDS-AML and overall poor prognosis. It is not uncommon for patients with Fanconi anemia to have easily detectable (oligoclonal) chromosomal alterations in their still normal (nonmalignant) marrow, which makes it even more challenging to determine the import of such alterations. We conducted a retrospective longitudinal analysis of fluorescent in situ hybridization (FISH) analysis for gains in 1q and 3q and for monosomy 7 and 7q deletions on 212 bone marrow samples from 77 children with FA treated at our institution between 1987 and 2007. Given the baseline increased chromosomal instability and defective DNA repair in patients with FA, which leads to unbalanced chromosomal aberrations such as deletions, insertions, and translocations, for the purpose of this analysis an abnormal clone was defined as ≥10% abnormal cells. Chromosome 3 and 7 aberrations were associated with increased risk of developing MDS-AML (P = 0.019 and P < 0.001 respectively), although the significance of chromosome 3 aberrations disappeared when different observation times were accounted for. Gain of 1q alone did not predict development of MDS-AML. In conclusion, children with FA should be followed closely with FISH analyses, because some of the clonal chromosomal abnormalities may be early indicators of progression toward MDS-AML and thus also of the need for hematopoietic stem cell transplantation.

Low dose decitabine in very high risk relapsed or refractory acute myeloid leukaemia in children and young adults

Low‐dose decitabine has encouraging activity and tolerability in adults with acute myeloid leukaemia (AML), but paediatric experience is lacking. We report our retrospective experience with decitabine in eight children and young adults (median age 4 years) with refractory/relapsed AML, who had failed multiple regimens or were not candidates for standard retrieval regimens due to prior toxicities. Three of eight patients (38%) had complete response (CR; 1 each of CR, CR with incomplete platelet recovery and CR with incomplete count recovery). Best responses were observed after a median of 2·5 cycles (range 1–4 cycles). Four patients received subsequent allogeneic stem cell transplant, and two remain in long‐term CR.

Response of NF1-related plexiform neurofibroma to High-Dose Carboplatin†

Plexiform neurofibromas (PN) are a hallmark of neurofibromatosis type 1 (NF1). These large nerve tumors can be disfiguring and surgery is the only known standard therapy. Surgical intervention may be suboptimal due to the diffuse nature of PN. Here, we present a case in which we describe the use of high‐dose carboplatin to treat the patients testicular seminoma which resulted in the decrease in size of a PN in a patient with NF1. Pediatr Blood Cancer 2011;56:488–490.